Histone acetylation dynamics regulating plant development and stress responses

Abstract

Crop productivity is directly dependent on the growth and development of plants and their adaptation during different environmental stresses. Histone acetylation is an epigenetic modification that regulates numerous genes essential for various biological processes, including development and stress responses. Here, we have mainly discussed the impact of histone acetylation dynamics on vegetative growth, flower development, fruit ripening, biotic and abiotic stress responses. Besides, we have also emphasized the information gaps which are obligatory to be examined for understanding the complete role of histone acetylation dynamics in plants. A comprehensive knowledge about the histone acetylation dynamics will ultimately help to improve stress resistance and reduce yield losses in different crops due to climate changes.

Introduction

In a eukaryotic nucleus, DNA is organized into a DNA–protein structure known as chromatin. A nucleosome is the central unit of chromatin consisting of 147 bp of DNA wrapped in ~ 1.7 turns around the histone proteins octamer, which is composed of two copies of each core histones H2A, H2B, H3, and H4 [1]. The amino-termini of these histones protrude out from the nucleosomal core structure and function as the preferred targets for different histone modifiers for a series of post-translational modifications (PTMs), including acetylation, methylation, phosphorylation, ubiquitylation, ADP-ribosylation, sumoylation, carbonylation and biotinylation. In addition to amino-terminal tails, the internal globular parts of histones are also subjected to PTMs. Several PTMs of histones regulate gene expression by modulating chromatin structure [2–4]. Hence, combinations of such modifications have been proposed to serve as a ‘histone code’ specifying a chromatin state that may govern the transcriptional status of genes [5].

Histone acetylation dynamics is one of the most studied PTM mechanisms. Like most of the other PTMs, acetylation is also reversible, which is dynamically modulated by the action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Generally, HATs cause gene activation through the addition of acetyl groups (CH₃COO-) onto the lysine residues of N-terminal tails [6–8] as well as globular domains [9, 10] of histones. On the other hand, these acetyl groups are removed by HDACs to counter the result of HATs by restoring the histones to its basal state, which mostly cause gene repression [6] (Figs. 1, 2). In rare exceptional cases, HATs and HDACs may cause repression and activation of genes, respectively [11–13]. Both HATs and HDACs target the lysine residues present in the histones, including H3K9, H3K14, H3K36, H4K5, H4K8, H4K12, and H4K16 to maintain the histone acetylation dynamics [8]. The histone acetylation dynamics create hyper- and hypo-acetylation, which are usually associated with gene activation and repression, respectively [6]. Histones may also be subjected to several other modifications apart from acetylation and deacetylation. The different combinations of specific modifications at various amino acid residues of nucleosomal histones have different effects on the local structure of chromatin that may lead to either activation or repression of the specific genomic loci [5, 14]. For instance, the combinations of histone acetylase/deacetylase complex with histone methylase/demethylase [15–17], chromatin remodelling complex [18, 19] and DNA methylase/demethylase complex [18, 20, 21] affect the transcriptional status of the genomic loci (Fig. 1).

Fig. 1.

Modulation of chromatin status by histone acetylation dynamics and other modifications. A combination of acetylation and methylation of different lysine residues in nucleosomal histones may cause expression (permissive chromatin) and repression (repressive chromatin) of genes. Besides, the combination of histone deacetylation and DNA methylation may also convert permissive chromatin to repressive chromatin which generally leads to gene repression. The regulation of gene expression is also affected by chromatin remodelling complex (such as SWI/SNF complex). Ac represents acetylation on lysine 4/9/14/27/36 of H3, and lysine 5/8/12/16 of H4 histone (H3K4/9/14/27/36 and H3K5/8/12/16), Me in the green coloured circles represent methylation on lysine 9/27 of H3 histone (H3K9/27), Me in the brown-coloured circles represent methylation on lysine 4 and 36 of histone H3 (H3K4/36), Me in the red coloured circles represent DNA methylation (cytosine methylation), SWI/SNF: SWITCH/SUCROSE NONFERMENTING chromatin remodelling complex. TFs transcription factors, RNA Pol. II RNA polymerase II. This is a simplified figure describing only combinatorial effect of histone acetylation and histone/DNA methylation and chromatin remodelling

Fig. 2.

Regulation of histone acetylation dynamics. HATs (histone acetyltransferases) transfer acetyl group from Acetyl Co-enzyme A (Acetyl-CoA) to the lysine residue of the histone proteins. In contrast, HDACs (histone deacetylases) remove acetyl groups from the acetylated lysine and form acetate as a by-product

Molecular mechanism of gene regulation by histone acetylation

Chromatin is dynamically organized into two-states, euchromatin and heterochromatin, which are interconvertible depending upon the stimuli. Euchromatin (loose structure) is an expressive state, while heterochromatin (compact structure) is a repressive state of gene expression. The compact structure of nucleosomes causes an obstacle for gene expression. Histone acetylation is a PTM that regulates chromatin structure and genome accessibility in collaboration with other histone modification(s) and DNA methylation. HATs act as coactivators, which are primed to the nucleosome by sequence-specific DNA-binding proteins. As shown in Fig. 1, HATs neutralize the positive charge of the core histones of the nucleosomes through the addition of acetyl groups (Fig. 2) and cause weakening of the DNA-histone interaction. This results in the switching from repressive (closed chromatin) to expressive state (open chromatin) of chromatin [22–24]. This conversion further allows the binding of RNA polymerase and transcription factors to the promoter region of the target genes for initiating their transcription. The promoter is the gene regulatory DNA stretch situated upstream of the transcription start site (TSS) [25]. The histone acetylation enrichment around TSS has been found to be positively correlated with the gene expression [26, 27]. On the other hand, the expressive state is converted to chromatin's repressive state by HDACs. HDACs act as the repressor proteins which are targeted on the active promoters through sequence-specific DNA-binding corepressor proteins. HDACs remove acetyl groups (Fig. 2) from the core histones of the nucleosomes and enhance the affinity between DNA and histones. The increased interaction between DNA and histones results in the compaction of chromatin structure, ultimately causing gene repression [28, 29] due to inaccessibility of the template DNA to the transcriptional machinery [30] (Fig. 1). Generally, histone acetylation is associated with gene activation and deacetylation is associated with the gene repression. However, these correlations are not always true. There are few reports that have shown association of HATs and HDACs with gene repression and activation, respectively [11–13]. This is because of the fact that the overall combination of histone modifications (acetylation, methylation, ubiquitination, phosphorylation, sumoylation, etc.) at different amino acid residues have different result on the chromatin structure and so on the process of transcription. Thus, the effect of HATs and HDACs is not always linear but combinatorial and it should be seen in the overall context of ‘histone code’.

Histone acetyltransferases

Histone acetyltransferases act as the “writer” by adding an acetyl group in the lysine residues of histones and generally cause gene activation. Histone acetyltransferases gene family having the varying number of members in different plants. There are 12 HATs in Arabidopsis [6], 32 in tomato [31], 6 in litchi [32], 7 in grape [33] and 8 in rice [34]. Based on sequence similarity and domains organization, HATs are subdivided into four groups; GNAT (General Control Non-depressible 5 (GCN5)-related Acetyltransferase), MYST (MOZ-YBF2/SAS3-SAS2/TIP60), CBP (cAMP-Responsive Element Binding Protein (CREB)-Binding Protein) and TAF_II250 (TATA-binding protein Associated Factor 1) [6, 35] (Fig. 3). These families are symbolized by the acronyms HAG, HAM, HAC, and HAF, respectively [6]. These HAT proteins possess different conserved domains such as ELP3 (elongator complex protein 3), HAT1 (histone acetyltransferase 1), Chromodomain and Znf-C2H2 in HAG/HAM, KIX (Kinase-inducible domain interacting), PHD (Plant Homeodomain), Znf-ZZ and Znf-TAZ in HAC and Bromodomain, UBQ and Znf-C2HC in HAF for their activity [6, 33, 36]. These conserved domains of HATs make them efficient by performing different functions, including interaction with RNA Pol II during transcript elongation (ELP3), histone acetylation (HAT1), recognizing and binding with a specific acetylated histone residue (Chromo- and Bromo-domain), protein-DNA or protein–protein interactions (Znf-C₂H₂ and Znf-C₂HC, Znf-ZZ and Znf-TAZ domain), interaction with histones and other histone-recognition proteins (PHD), binding with the transactivation domain of transcription factors (KIX domain) and binding with acetylated histone lysine residues [6, 34]. Thus, HATs form multiprotein complexes through physical interaction with other co-factors, including transcription factors, activator proteins, and histone modifiers to control gene expression [23].

Fig. 3.

A summary of the function of different HATs (a) and HDACs (b) in plants. Based on domain arrangements, HATs are categorised into GNAT, MYST, CBP and TAFII250 proteins. Similarly. HDACs are divided into groups of SIR2, RPD3-type and HD2-type proteins. This classification is mainly based on Arabidopsis. The green and red lines represent positive (activation) and negative (suppression) of the biological processes, respectively. Two-letters in bracket represent the name of plant species. HATs histone acetyltransferases, GNAT general control non-depressible 5 (GCN5)-related acetyltransferase, MYST MOZ-YBF2/SAS3-SAS2/TIP60, CBP cAMP-responsive element binding protein (CREB)-binding protein, TAFII250 TATA-binding protein associated factor 1, HDACs histone deacetylases, RPD3 reduced potassium dependency 3, HDA histone deacetylase, SIR2 silent information regulator 2, HD2 histone deacetylase 2. The red-coloured name of genes showed no recent reports on the respective gene

Histone deacetylases

Histone deacetylases work as the “eraser”, which removes an acetyl group from the acetylated lysine residues of the core histones added by the HATs. Generally, deacetylation causes gene repression to regulate numerous biological processes. Just like HATs, the number of HDACs also varies in different plant species. For instance, there are 18 HDACs in Arabidopsis [6], 14 in tomato [31], 11 in litchi [32], 13 in grape [33], 28 in soybean [37], 30 in upland cotton [38] and 18 in rice [39]. Based on their sequence similarity, the HDAC family is comprised of three sub-families; RPD3/HDA1 (Reduced Potassium Dependency 3/histone deacetylase 1), SIR2 (Silent Information Regulator 2) and a plant-specific HD2 (histone deacetylase 2) (Fig. 3). The RPD3 (histone deacetylase; HDA2/5/6/8/9/14/15/18/19), SIR2 (SRT1/2) and HD2 (HD2A/B/C/D) members possess conserved histone deacetylase domain. Several members of HDACs also possess the Znf (zinc finger) motif which helps in protein–protein interactions [6, 32, 33, 38]. Most of the HDAC proteins lack the DNA binding domain and form the multiprotein repressor complex with other co-factors (transcription factors and or repressor proteins) to regulate different biological processes.

Functions of histone acetylation

Several reports have revealed the role of histone acetylation in the development and adaptation of plants during different stresses by regulating a specific set of genes for a specific purpose as shown in Fig. 3 and listed in Tables 1 and 2. Histone acetylation is also involved in the maintenance of genome stability through the regulation of transposons. In the following sections, we have discussed different processes that are regulated by histone acetylation dynamics.

Table 1.

Summary of known HAT and HDAC protein complexes crucial for the plant growth and development

HAT/HDAC complex	Target genes	Associated lysine moiety	Role	Plant	Reference
Seed germination and seedling development
HDA15-PIF1	Light-responsive genes	H3ac	Seeds germination in the dark	Arabidopsis	[28]
HDA15-PIF3	Photosynthesis-related genes	H3 and H4ac	Seeds germination in the dark	Arabidopsis	[48]
HDA15-HY5	XTH15, EXP2, and IAA19	H4ac	Photomorphogenesis and hypocotyl cell elongation	Arabidopsis	[49]
HDA9-HY5	ATG5 and ATG8e	H3K9/K27ac	Seedling development	Arabidopsis	[29]
HDA19-SUVH5	ABI3, RGA, DOG1	H3ac and H3K9me2	Seed dormancy	Arabidopsis	[16]
HDA19-SCL15	LEC1 and ABI3	H3K9/K14ac	Seedling development	Arabidopsis	[50]
HDA19-BES1-TPL	ABI3	H3ac	Early seedling development	Arabidopsis	[51]
HDA6-HDA19	LEC1, FUS3, and ABI3		After seed germination	Arabidopsis	[52]
Vegetative growth
GCN5-ADA2-WOX11	PIN9, EXPA23, CESA9, CSLF6, GLU5, BGLU5, ALDO		Crown roots development	Rice	[55]
HDA9-PWR-HOS15	ERF6 and KINASE2	H3K27/K36/K56ac	Plant development	Arabidopsis	[53]
HAG1-ADA2b			Regulation of leaf development and trichome morphogenesis	Arabidopsis	[57]
HDA6-AS1	KNOX gene (KNAT1, KNAT2, and KNATM)	H3ac	Leaf development	Arabidopsis	[58]
HDA19-SCR	BR6OX2	H3 and H4ac	Root cortical cell fate	Arabidopsis	[60]
HDA6-LDL1/2-TOC1	CCA1/LHY	H3ac	Circadian clock	Arabidopsis	[15]
HDA9-ELF3	TOC1	H3ac	Circadian clock	Arabidopsis	[64]
Flowering and reproductive organs development
HAM1/2-MRG1/2	FLC	H4ac	Regulates flowering	Arabidopsis	[17, 66]
HD2C-MRG1/2	FT	H3K9/K23/K27ac	Flowering	Arabidopsis	[68]
HDA19-AP2-TOPLESS	AG, AP3, PI, SEP3	H3K9/H3K4/K16ac	Floral organ development	Arabidopsis	[69]
HDA9-LUX-HOS15	GI	H3ac	Photoperiodic flowering	Arabidopsis	[72]
HDA9-PWR	AGL19	H3ac	Regulates flowering	Arabidopsis	[73, 74]
HDA9-PRC2	FLC	H3K27me3	Regulates flowering	Arabidopsis	[75]
HDA5-HDA6-FVE-FLD	MAF1-2	H3K9/14ac	Regulates flowering	Arabidopsis	[80]
HAM1/2		H4K5ac	Male and female gametophyte development	Arabidopsis	[82]
HDA8-ARID1	DUO POLLEN1 (DUO1)	H3K9ac	Controls sperm cell formation	Arabidopsis	[83]
Fruit ripening and aging
HDA1-ERF11	MaACO1, MaEXP2, MaEXP7 and MaEXP8	H3 and H4ac	Fruit ripening	Banana	[87]
CpHDA3- CpERF9	CpPME1, CpPG5	H3 and H4ac	Fruit ripening	Papaya	[91]
HDA9-PWR-WRKY53	WRKY57, APG9, and NPX1	H3K9/K27ac	Regulation of aging	Arabidopsis	[94]

Table 2.

Summary of known HAT and HDAC protein complexes have a vital role in different biotic and abiotic stress responses in plants

HATs/HDACs complex	Target genes	Associated histone marks	Functions	Plant	Reference
Biotic stress responses
HDA19-WRKY38/62	PR1		Fine-tuning of basal defence-responses	Arabidopsis	[96]
HAC-NPR1-TGA	PR	H3ac	Immunity	Arabidopsis	[98]
HDA9-HOS15	SNC1	H3K9ac	Immunity	Arabidopsis	[99]
GCN5-ADA2-EPBM1	ECR	H3K4/K9/K14/K27ac and H4K5ac,	Cuticular wax biosynthesis	Wheat	[101]
TaHDA6-TaHOS15-TaHDT701	TaPR1, TaPR2, TaPR5, and TaWRKY45	H3K9/H4K16ac	Defence-responses against Blumeria graminis	Wheat	[102, 103]
Abiotic stress responses
GCN5-ADA2b-AREB1	NAC6/7/120,	H3K9ac	Drought responses	Populus	[23]
ZmGCN5-ZmHATB	ZmEXPB2 and ZmXET1	H3K9ac	Salt stress responses	Maize	[107]
HDA15-MYB96	ROP6/10/11	H3 and H4ac	ABA signalling and early-stage stress responses	Arabidopsis	[126]
HDA19-MSI1	PYL1, PYL4, PYL5, PYL6	H3K9ac	ABA signalling	Arabidopsis	[127]
HDA9-ABI4-PWR	CYP707A1/2		ABA homeostasis	Arabidopsis	[132, 133]
HDA9-PWR	PIF4, YUCCA8	H3K9ac	Thermogenesis	Arabidopsis	[13]
HDA15-HFR1	PIF4, HB2, XTR7	H3K14ac	Heat stress	Arabidopsis	[118]
HDA6-HD2C	ABI1/2	H3K9/K14ac	ABA and salt responses	Arabidopsis	[114]
SRT1/2- ENAP1	ETHYLENE RESPONSIVE GENES	H3K9ac	Ethylene signalling	Arabidopsis	[121]
HD2C-HOS15	CORs	H3ac	Cold stress-responses		[122]
HD2C-BRAHMA	HSP101 and HSFA3	H4K16ac	Heat stress-responsive	Arabidopsis	[19]
HDA1-IDS1-TPR1	SOS1, LEA1	H3ac	Salt stress-responses	Rice	[136]
MaHDA2-MaMYB4	MaFAD3-1, MaFAD3-3, MaFAD3-4 and MaFAD3-7	H3 and H4ac	Cold stress-responses	Banana	[142]

Maintenance of genome stability

Transposable elements (TEs) are itinerant DNA sequences that destabilize genome integrity through genome colonization. Acetylation of histones H3 and H4 and tri-methylation of lysine 4 of H3 (H3K4me3) are associated with the expression of TEs [40]. There are reports which showed that these TEs may be suppressed through different epigenetic modifications such as histone deacetylation and demethylation and DNA methylation in plants. For instance, in Arabidopsis, histone deacetylase 6 (HDA6) represses TEs through H3K9 deacetylation and methylation [41]. For this purpose, HDA6 interacts with SUVH4/5/6 (SUV(VAR)3–9 HOMOLOG 4/5/6). Similarly, a direct interaction of HDA6 with MET1 (methyltransferase 1) has been implicated in the silencing of TEs by controlling the status of histone acetylation and methylation and DNA methylation [40]. HDA6 and MET1 together regulate a large set of TEs and repeat sequences in Arabidopsis. Interaction of HDA6 with nuclear matrix protein TEK (TRANSPOSABLE ELEMENT SILENCING VIA AT-HOOK) and retinoblastoma-associated proteins FVE/MSI5 (MULTICOPY SUPPRESSOR OF IRA1 5) maintains genome integrity by suppressing the TEs and repeat-containing genes [42, 43]. Besides, HDA6 along with CHROMATIN REMODELING COMPLEX SUBUNIT B, SWI3B (SWITCH SUBUNIT 3) silences the transposable elements through H3K9 deacetylation [44]. HDA6 also causes gene repression through RNA-directed DNA methylation (RdDM) [45]. However, the IDM1 (INCREASED DNA METHYLATION 1)-mediated histone acetylation of H3K18 and H3K23 lysine residues enables the recruitment of DNA demethylase ROS1 (REPRESSOR OF SILENCING 1) to antagonize the RdDM at active DNA methylated sites [21]. In rice, deacetylation of lysine 9 of histone H3 (H3K9) by OsSRT1 (SIRTUIN 1) is implicated in transposon repression, DNA fragmentation, cell death and starch accumulation during seed development [46, 47] (Fig. 3). Thus, based on these recent studies, it can be concluded that both HDA6 and SRT1 deacetylate H3K9 residue and coordinate with histone and DNA methyltransferases to repress TEs and maintain genome stability in different plants [40–44, 46, 47]. There is a possibility that they might be physically interacting and functioning in the same complex. However, a molecular link between HDA6 and SRT1 is missing at present. Thus, the establishment of a relationship between them would help a better understanding of TEs repression and genome stability mechanism.

Regulation of plant development

Histone acetylation is an epigenetic modification that regulates different biological processes essential for the growth and development of plants. As summarized in Fig. 3, several recent studies have explored the role of HATs and HDACs in the growth and development are discussed below.

Vegetative growth and development

Vegetative growth is an essential phase of the plant’s life cycle and has a considerable impact on productivity. Various studies have suggested the role of histone acetylation in the development of different vegetative organs (Fig. 3; Table 1).

Seed germination and seedling development

Seed germination and seedling development are the early phases of the plant’s life cycle and light plays a very crucial role during these stages. HDA15 (histone deacetylase 15) is a light-regulated histone deacetylase, which interacts with PIF1 (PHYTOCHROME INTERACTING FACTOR 1) to suppress the light-responsive genes during seed germination in dark [28]. In the dark, HDA15 also restricts chlorophyll biosynthesis- and photosynthesis-related genes through its interaction with PIF3 [48]. Further, HDA15 with HY5 (ELONGATED HYPOCOTYL 5) also regulates photomorphogenesis by suppression of the hypocotyl cell elongation via H4 deacetylation of target genes involved in cell wall organization and auxin signalling in Arabidopsis [49]. HY5 also coordinates with histone deacetylase HDA9 (HISTONE DEACETYLASE 9) during photomorphogenesis. HDA9 and HY5 act synergistically to repress autophagy genes (ATG5 and ATG8e) through deacetylation of H3K9 and H3K27. Expression of ATG genes is upregulated due to degradation of HDA9-HY5 complex during transition from light to dark and nitrogen starvation conditions [29]. Another histone deacetylase, HDA19 interacts with histone methyltransferase SUVH5 (SU(VAR)3–9 HOMOLOG 5) and regulates seed dormancy through ABA and GA signalling pathways by modulating overall histone H3 acetylation and H3K9me2 methylation on the promoter of the target genes ABI3 (ABA INSENSITIVE 3), RGA (REPRESSOR OF GA) and DOG1 (DELAY OF GERMINATION 1) [16]. HDA19 also interacts with SCL15 (SCARECROW-LIKE 15) to represses embryonic traits in the developing seedlings [50]. It forms a repressor complex with BES1 (BRI1-EMS-SUPPRESSOR 1) and TPL (TOPLESS) to regulate ABI3 expression in the early seedling development governed by ABA signalling [51]. After seed germination, HDA19 (HISTONE DEACETYLASE 19) and HDA6 (HISTONE DEACETYLASE 6) together suppress embryo-specific transcription factors like LEC1 (LEAFY COTYLEDON 1), FUS3 (FUSCA3), and ABI3 [52]. On the other hand, HDA9 interacts with PWR (POWERDRESS) and HOS15 (HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 15) to suppress the expression of the target genes and ultimately governs developmental processes in Arabidopsis [53].

Meristems

In plants, meristems are the primary source of all the tissues and organ development. A histone acetyltransferase GCN5 of Arabidopsis has been found to control the shoot apical meristem through regulation of meristem-regulatory genes, including WUS (WUSCHEL), LEAFY, and UFO (UNUSUAL FLORAL ORGANS) [54]. The homolog of AtGCN5 in rice regulates crown root meristem by acetylating H3 on the crown root-specific genes. GCN5 forms a ternary protein complex with ADA2 (ALTERATION/DEFICIENCY IN ACTIVATION 2) and WOX11 (WUSCHEL-RELATED HOMEOBOX 11). The GCN5-ADA2-WOX11 module activates the target genes involved in auxin transport (PIN-FORMED; OsPIN9), cell wall biosynthesis (EXPANSIN A23; OsEXPA23, CELLULOSE SYNTHASE A CATALYTIC SUBUNIT 9; OsCESA9, CELLULOSE SYNTHASE-LIKE F; OsCSLF6 and ENDO-1,4-BETA GLUCANASE 2; OsGLU5) and energy metabolism (β-GLUCOSIDASE; Os1BGLU5 and Os9BGLU33 and ALDOLASE; OsALDO) in the crown roots [55]. In azalea also, histone H4 deacetylation and DNA methylation has been reported to reorganize the chromatin to regulate Shoot Apical Meristem (SAM)-regulatory genes and control the vegetative growth and floral differentiation [56].

Leaf and root development

Leaf is an essential part that performs photosynthesis, and it generates food and energy for the whole plant. Thus, its development is very crucial for plant growth and cellular processes. The transcriptional adapter ADA2b (ALTERATION/DEFICIENCY IN ACTIVATION 2b) stimulates the transferase activity of GCN5 (HAG1) to regulate leaf development and trichome morphogenesis. HAG1 and ADA2b are also required for the coupling of endoreduplication and trichome branching in Arabidopsis [57]. Leaf development is also controlled by the synchronized action of HDA6 and AS1 (ASYMMETRIC LEAVES 1), which regulates the expression of KNOX (KNOTTED1-LIKE HOMEOBOX) genes KNAT1, KNAT2 (KNOTTED-LIKE FROM ARABIDOPSIS THALIANA 1/2), and KNATM (KNOTTED-LIKE FROM ARABIDOPSIS THALIANA MEINOX) [58].

AtGCN5 increases the expression of the root-meristem gene loci, including WOX5/14 (WUSCHEL RELATED HOMEOBOX 5/14), SCR (SCARECROW), and PLT1/2 (PLETHORA 1/2) through histone acetylation during callus development [59]. The histone deacetylase, HDA19 forms a repressor complex with SCR to suppress the expression of BR (Brassinosteroid) biosynthesis gene BR6OX2 (BRASSINOSTEROID-6-OXIDASE 2), which ultimately determines root cortical cell fate in Arabidopsis [60]. In Arabidopsis, a plant-specific HDAC, HDT1 controls stem vascular tissue development by regulating cell proliferation and differentiation [61], while RPD3-type HDAC, HDA19 controls the root cell elongation and modulates phosphate starvation responses [62].

Circadian cycle

Circadian rhythms occur in plants to synchronize with the light cycle of its surroundings. These rhythms are controlled by a set of genetic and epigenetic regulators including HATs and HDACs. HDA6 forms a repressor complex with histone demethylase LDL1/2 (LYSINE-SPECIFIC HISTONE DEMETHYLASE LIKE 1/2) and circadian clock protein TOC1 (TIMING OF CAB EXPRESSION 1). This complex represses expression of CCA1 (CIRCADIAN CLOCK ASSOCIATED 1) and LHY (LATE ELONGATED HYPOCOTYL) genes and ultimately controls circadian rhythm [15]. Whereas, HDA6-LDL1/2 complex also physically interacts with CCA1/LHY to repress the TOC1 expression [63]. A recent study showed that the HDA9 and EARLY FLOWERING 3 (ELF3), an evening complex (EC) component, interacts with each other to regulate the declining phase of TOC1 after its peak expression [64]. These studies indicate that HDA6 and HDA9 might be working antagonistically to regulate the circadian rhythm during plant development. So, the insight into the establishment of the correlation between HDA6 and HDA9 will be helpful to a better understanding of the circadian rhythm.

Regulation of flowering

Flower is a fundamental structure of the reproductive stage of plants. Its differentiation is a transition from the vegetative to the reproductive phase [65]. Several genetic and epigenetic regulators govern this transition. FLC (FLOWERING LOCUS C) is a negative genetic regulator of flowering, which is highly expressed during the vegetative phase and is suppressed during the reproductive period [11, 17, 66]. Recent studies have elucidated that histone acetylation modulation by different HAT and HDAC epigenetic modifiers is responsible for the regulation of flowering in different plants. The acetylation of H3K9 on the FLC locus enhances its expression causes delayed flowering [67]. Also, the MYST histone acetyltransferase HAM1/2 enhances the expression of the FLC gene through H4K5 acetylation and results in delayed flowering [66]. In another study, it was shown that HAM1/2 interacted with histone methylat-ion reader proteins MRG1/2 (MORF RELATED GENE 1/2) to elevate the expression of flowering genes FLC and FT (FLOWERING LOCUS T) through bridge formation between two histone modifications, histone H4 acetylation and trimethylation of H3K36 [17]. On the other hand, a plant-specific histone deacetylase HD2C, along with MRG1/2, suppresses FT (FLOWERING LOCUS T) expression in the dark to control flowering [68]. These recent studies indicate that MRG1/2-dependent HAT and HDAC complexes mediate histone acetylation dynamics to modulate FLC and FT expression and so control the photoperiodic flowering pathway. Histone acetyltransferases usually cause gene activation. However, AtHAC1 regulates flowering time by suppressing the FLC expression in Arabidopsis [11]. There is a possibility that AtHAC1 might be inducing expression of any repressor factors acting upstream of the FLC gene.

The physical interaction of HDA19 with AP2 (APETALA 2) and TPL (TOPLESS) suppresses floral organ identity genes AGAMOUS, APETALA3, PISTILLATA, and SEPALLATA3 to control the flower development [69]. Recent studies suggest that HDA19 controls flowering time in a photoperiod-dependent manner [70]. On the other hand, a plant-specific histone deacetylase HD2D is responsible for the delayed flowering in a photoperiod-independent manner in Arabidopsis [71]. These reports indicate that HDA19 and HD2D might be working differently to control the flowering time in a photoperiod-dependant and independent manner. Several studies implicate that HDA9 suppresses flowering. It forms a repressor complex with LUX and HOS15 to regulate photoperiod-dependent flowering via transcriptional repression of GI (GIGANTEA) [72]. HDA9 also interacts with PWR (POWERDRESS) and controls flowering time by repression of AGL19 (AGAMOUS-LIKE 19) expression through histone H3 deacetylation [73, 74]. However, a recent study showed that HDA9 accelerated flowering by deacetylating H3K27 lysine residues, which is essential for PRC2 (POLYCOMB REPRESSIVE COMPLEX 2)-mediated trimethylation of H3K27 to suppress FLC expression in Arabidopsis [75]. Auxin signalling is important for flower development and subsequent silique development. It has been shown that the histone acetylation dynamics facilitate auxin signalling. HDA9 co-ordinates with HDA6 to regulate valve cell elongation by modulating the auxin signalling pathway during silique formation [76, 77]. In common bean, HDA6 is upregulated in flowers and pods suggesting its role in the development [78]. AtHDA6 physically interacts with FLD and suppress the FLC and MAF4 expression to control the flowering [79]. Another report showed that the AtHDA5 histone deacetylase forms a repressor complex with HDA6, FVE, and FLD (FLOWERING LOCUS D) and plays a decisive role in controlling flowering in Arabidopsis. This complex represses the expression of FLC and MAF1-2 (MADS-BOX AFFECTING FLOWERING GENES 1–2) by the deacetylation of H3K9 and H3K14 lysine residues [80]. Also, the knockdown of GhHDA5 was found to be responsible for delayed flowering in the cotton RNAi lines suggesting its pivotal role in the regulation of flowering time [38] (Fig. 3; Table 1). In azalea also, a combination of H4 acetylation and DNA methylation has been shown to reorganize the chromatin to regulate genes essential for floral differentiation [56]. Acetylation of K36 residue of H3 (H3K36ac) is conserved lysine acetylation across the plant kingdom and the actions of GCN5 and HDA19 have been found to antagonistically regulate its homeostasis [81]. It is profoundly enriched in the euchromatin regions, especially at the 5′ end (just downstream to the TSS) of the active genes overlapping with H3K36me3 histone methylation and H2A.Z histone variants.

Gamete development

Gametes are the essential structure for sexual reproduction. Unlike animals, where meiotic product directly forms the gametes, the germline in plants is established by two successive mitotic divisions after completion of meiosis. The HAM1/2 proteins are MYST histone acetyltransferases that regulate the mitotic cell cycle at the early stages of gametogenesis and so play an essential role in the development of male and female gametophyte in Arabidopsis [82]. On the other hand, histone deacetylase HDA8 interacts with ARID1 (AT-RICH INTERACTING DOMAIN 1) protein to control sperm cell formation by regulating the expression of DUO POLLEN1 (DUO1) gene, an important regulator of male germline development [83]. Another HDAC, AtHDA7, has been found to control ARABIDOPSIS HOMOLOG OF SEPARASE (AtAESP) expression for female gametophyte and embryo development [84] (Fig. 3; Table 1).

Fruit ripening

Fruit development and its ripening involve different cellular, metabolic and molecular processes that determine fruit growth, fruit softening and accumulation of soluble sugars, aromatic volatile compounds and pigments in it. These processes are controlled by both genetic and epigenetic mechanisms. In pear fruits, sugar accumulation has been regulated by the histone acetyltransferase HLS1 (HOOKLESS1). HLS1 positively regulates the expression of WRKY31 by histone acetylation on its promoter. Further, WRKY31 binds to the promoter and induces the transcription of a sugar transporter gene SWEET15, a positive regulator required for sugar accumulation in the fruits [85]. Ethylene is an essential phytohormone obligatory for the fruit ripening in climacteric (e.g., banana and tomato fruits) but not in non-climacteric (e.g., pear and orange fruits) fleshy fruits [86]. Several reports suggest that ethylene biosynthesis and signalling are regulated by histone acetylation dynamics. In banana, HDA1 physically interacts with ERF11 and delays fruit ripening by repressing ethylene biosynthesis gene MaACO1 and the ripening-related Expansin genes MaEXP2, MaEXP7, and MaEXP8 [87] (Table 1). Thus, HDA1 inhibits ethylene signalling. On the other hand, another HDAC MaHDA6 promotes ethylene signalling and fruit ripening by repressing ERF11/15 genes [88]. Similarly, in tomato, different HDACs have different effects on fruit ripening. SlHDA3 functions as an inhibitor of fruit ripening by controlling ethylene biosynthesis [89] whereas SlHDT3 induces ethylene and carotenoid accumulation leading in fruit ripening [90]. In papaya, CpHDA3, which is an RPD3 type histone deacetylase, interacts with ERF9 to form a repressor complex that represses the expression of PECTIN METHYLESTERASE (PME1) and POLYGALACTURONASE (PG5) genes during fruit ripening and softening [91] (Table 1).

Aging

Leaf senescence is an age-dependent and environment stimulated catabolic process. It is a complex and programmed mechanism that leads to degradation of the macromolecules like nucleic acid, proteins and lipids into micronutrients. The micronutrients obtained by the degradation of macromolecules are used by the other developing organs, including young leaves, reproductive organs, and seeds. Several genetic and epigenetic regulators, including HATs and HDACs, have been reported to control the metabolic transition and nutrient recycling during senescence. The CREB-binding type histone acetyltransferase HAC1 has been found to regulate the process of senescence in Arabidopsis [92]. Around 43 genes, including ERF22, which is required for leaf senescence, have been found to be regulated by HAC1 during age-related senescence by the acetylation of H3K9 on their promoters [92]. On the other hand, mutant and RNAi plants of histone deacetylase HDA6 displayed increased leaf longevity [93]. Another HDAC, HDA9 forms a repressor complex with PWR and WRKY53 to suppress the expression of genes for inhibitors of senescence and thus monitors the process of aging in Arabidopsis [94] (Table 1).

Responses to different stresses

In their lifetime, plants cope up with different biotic and abiotic stresses. These stresses affect plant growth, development and productivity. Being sessile, plants cannot avoid these stresses. Instead, they sense the stress and respond by activating different signalling pathways leading to physiological and developmental adaptations. Several recent studies have shown that the HATs and HDACs are critical epigenetic regulators involved in the various biotic and abiotic stress responses assisting in plant adaptation during different stress conditions.

Regulation of biotic stress responses

Biotic stress can be caused by different pathogens leading to damage in the host plants, ultimately imposing a penalty on the yield. Numerous studies substantiate the role of different HATs and HDACs involved in biotic stress responses, increasing plant immunity against the causal organisms. Plant hormones like salicylic acid (SA), jasmonic acid (JA) and ethylene play a critical role in response to biotic and abiotic stresses. A recent study in Arabidopsis demonstrated that the GCN5 regulates SA-responsive genes by increasing the level of H3K14ac on their promoters in response pathogen challenge [27]. On the other hand, genes involved in JA and ethylene signalling in response to pathogen attack have been found to be regulated by HDA19 [95]. HDA19 also interacts with WRKY38 and WRKY62 to fine-tune the basal defense-responses by inhibiting the SA signalling [96]. A plant-specific histone deacetylase HD2B is phosphorylated by MPK3 (MITOGEN-ACTIVATED PROTEIN KINASE 3) upon pathogen (Pseudomonas syringae pv. tomato DC3000 (Pst DC3000)) infection to move from the nucleolus to the nucleoplasm [97]. Thus, the HD2B-MPK3 module maintains a basal level of several defense-related genes tomaintain the basal level of innate immunity. Accordingly, the hd2b mutant plants are more susceptible to the pathogen. The CBP/p300-type histone acetyltransferases AtHAC1/5 forms a coactivator complex with NPR1 (NON-EXPRESSER OF PR GENES 1) and TGA (TGACG- BINDING FACTOR) to activate transcription of PATHOGENESIS RELATED (PR) genes [98]. This acetylation-mediated epigenetic reprogramming eventually provides immunity to the host plants against Pst DC3000. On the other hand, a histone deacetylase HDA9 debilitates innate immunity by physically interacting with HOS15 [99]. The HDA9-HOS15 complex represses NLR (NOD-LIKE RECEPTOR) and SNC1 (SUPPRESSOR OF npr1-1, CONSTITUTIVE 1) expression via H3K9 deacetylation during the infection of Pst DC3000 pathogen. Cuticular wax is an essential constituent of the surface cuticle that plays a crucial role in protecting the plants from different environmental stresses. In Arabidopsis, GCN5 modulates wax biosynthesis-related gene CER3 (ECERIFERUM3) expression by acetylation of H3K9/14 lysine residues [100]. In wheat, GCN5 forms a complex with ADA2 and EPBM1 (ECR PROMOTER-BINDING MYB TRANSCRIPTION FACTOR1) to activate the transcription of ECR (ENOYL-COA REDUCTASE) gene, which encodes for a key constituent of cuticular wax [101]. During wax biosynthesis, GCN5-ADA2-EPBM1 histone acetyltransferase complex activates ECR expression via acetylation of H3 and H4 histones. The fungus Blumeria graminis f.sp. tritici (Bgt) targets this cuticular wax for its conidia germination causing powdery mildew [101]. During Bgt infection, HDA6 and HOS15 associate to constitute a repressor complex that suppresses the defense-related genes TaPR1, TaPR2, TaPR5 (Pathogenesis-Related1/2/5), and TaWRKY45. These genes play a crucial role in the plant defense against Bgt [102]. Other HDAC, TaHDT701 associates with HDA6-HOS15 complex to suppress PR1/2/5 genes during Bgt infection [103]. Thus, these results reveal that histone deacetylases HDA6 and HDT701 are negative regulators of innate immunity in wheat. In rice also, HDT701 weakens the innate immunity through suppression of PRR (PSEUDO-RESPONSE REGULATOR) and defense-related genes by deacetylating histone H4 on their promoter [104]. DNA methylation is a gene silencing method that defends against viral infection. In tobacco, V2 protein of Tomato yellow leaf curl virus (TYLCV) interacts directly with NbHDA6 which is involved in gene silencing in cooperation with MET1 (METHYLTRANSFERASE 1) [20] (Fig. 3; Table 2). Surprisingly, only a few recent studies have reported the role of HATs in plant immunity. More research is required in this area to gain deeper insights into the role of HATs in regulating plant immunity.

Regulation of abiotic stress responses

Plants face different abiotic stresses (drought, salinity, heat, cold, etc.) responsible for the decline in growth and development, which ultimately causes loss of crop productivity. Numerous studies have shown that the histone acetylation dynamics plays a crucial role in controlling the stress responses facilitating plant adaptation in adverse conditions (Fig. 3; Table 2).

Salt and drought stress

Salt and drought stresses are known to inhibit plant growth and reduce the overall productivity. Numerous recent studies suggest that several HATs/HDACs have been involved in the salt and drought stress-responses in plants. The gcn5 mutants were susceptible to salt stress due to disintegrated cell wall [105]. In Arabidopsis, AtGCN5 regulates expression of MYB54, CTL1 (CHITINASE-LIKE PROTEIN 1), and PGX3 (POLYGALACTURONASE INVOLVED IN EXPANSION3) through H3K9/14ac providing salt stress tolerance. Moreover, GCN5-mediated histone acetylation also plays an essential role in the phosphate starvation responses (PSR) through At4–miR399–PHO2 pathway [106]. In Populus trichocarpa, GCN5 forms a protein complex with ADA2b and AREB1 (ABA-RESPONSIVE ELEMENT BINDING PROTEIN 1) and regulates the expression of drought-responsive genes such as NAC006, NAC007, and NAC120 through enhancement of H3K9ac to confer the drought tolerance [23]. In maize, ZmGCN5 and ZmHATB increase the expression of cell wall-related genes ZmEXPB2 (EXPANSIN B2) and ZmXET1 (XYLOGLUCAN ENDOTRANSGLUCOSYLASE 1) through H3K9 hyperacetylation on the promoter region during salt stress [107]. Thus, GCN5 is a versatile epigenetic regulator that provides tolerance against different stresses in plants. Another histone acetyltransferase HAG3 has been reported to impede the UV-B-induced DNA damage repair and signalling in Arabidopsis [108]. On the other hand, GNAT-MYST activates wound-induced cellular reprogramming-related crucial genes, including WIND1 (WOUND INDUCED DEDIFFERENTIATION 1), ERF113/RAP2.6 L (ETHYLENE RESPONSIVE FACTOR113/ RELATED TO AP2 6L), and LBD16 (LATERAL ORGAN BOUNDARIES-DOMAIN 16) through histone acetylation [109]. A positive effect of AtHAC1 on gene transcription was demonstrated by activating the endogenous promoter activity of AREB1 (ABA-RESPONSIVE ELEMENT BINDING PROTEIN 1) through CRISPRa dCas9^HAT strategy. There was upregulation of RD29A (RESPONSIVE TO DESICCATION 29A) expression in the CRISPRa dCas9HAT harbouring transgenic plants resulting in increased drought tolerance in Arabidopsis [110]. The upregulation of four histone acetyltransferases OsHAC703, OsHAG703, OsHAF701, and OsHAM701 and hyperacetylation at H3K9, H3K18, H3K27 and H4K5 lysine residues during drought stress suggest an involvement of HATs in the drought responses in rice [111] (Fig. 3; Table 2). HDA9 reduces the plant sensitivity to drought and salinity stresses by decreasing the H3K9ac level of the stress-responsive genes [112]. This function is an antagonist to WRKY53 function [113]. HDA6 interacts with HD2C to regulate the ABA- and salt stress-responsive genes through modulation of H3K9ac and H3K14ac lysine residues in Arabidopsis [114] and also controls the drought-responsive network through regulation of JA signalling [115].

Heat and cold stress

Worldwide, unexpected fluctuations in temperature are causing significant loss of crop productivity. There are several studies which suggest that HATs/HDACs are involved in responses to heat and cold stresses in plants. GCN5 provides thermotolerance by activating the expression of HSFA3 (HEAT SHOCK TRANSCRIPTION FACTOR A 3) and UVH6 (ULTRAVIOLET HYPERSENSITIVE 6) genes through H3K9/14 hyperacetylation on their promoter [116]. HAC1 has been found to maintain or restore the expression level of several viral and housekeeping genes through interaction with other activators like HsfB1 providing heat stress tolerance in tomato [117].

Several plants respond to the unfavourable high ambient temperature and try to facilitate cooling (thermomorphogenesis) through auxin signalling. In Arabidopsis, HDA9 forms complex with PWR and deacetylates H3K9 on the promoter of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and YUCCA8 (YUC8) to control the thermomorphogenesis [13]. In addition, another study has revealed that HDA9 activates YUCCA8 expression by net eviction of H2A.Z histone variants leading to PIF4 binding on its promoter. This enhances auxin production and thermomorphogenesis [12]. HDA15, another HDAC that interacts with HFR1 (LONG HYPOCOTYL IN FAR RED1) and represses the warm-temperature responsive genes at normal temperature [118]. The hda6 plants show hypersensitivity to heat exposure [119]. HDA6 plays an essential role in freezing tolerance [120]. The two SIR-type HDACs SIRTUIN1/2 (SRT1 and SRT2) physically interact with the EIN2 NUCLEAR ASSOCIATED PROTEIN1 (ENAP1) to regulate the ethylene-responsive genes in Arabidopsis [121]. The HD2C interacts with a WD4-repeat protein HOS15 and CBFs (C-REPEAT BINDING FACTORS) during normal temperature to suppress the expression of COR (COLD-RESPONSIVE) genes COR15A and COR47. During cold, HOS15 facilitate ubiquitin-mediated degradation of HD2C, leading to the recruitment of CBFs on the promoter of COR genes for increasing their expression through hyperacetylation of histones [122]. HD2C also regulates heat stress-responsive genes. For this, HD2C coordinate with BRAHMA (BRM)-containing SWITCH/SUCROSE NONFERMENTING (SWI/SNF) chromatin remodelling complex [19]. Thus, HD2C is a suppressor of heat stress-responsive genes. However, another plant-specific histone deacetylase HD2D required for the regulation of the stress responses in Arabidopsis [123]. A cotton homolog of HD2D, GhHDT4D plays important role to regulate drought responses by deacetylation of H3K9 marks on the promoter, leading to the suppression of WRKY33, a suppressor of the drought responses in cotton [124, 125] (Fig. 3; Table 2).

ABA signalling

ABA is an essential hormone required for stress tolerance, and its signalling plays a dynamic role in adapting plants during different stresses. The ROP (RHO OF PLANTS) family of proteins such as ROP6, ROP10, and ROP11 regulate ABA signalling at the early stages of stress [126]. The HDA15-MYB96 protein complex suppresses these genes through deacetylation of H3 and H4 histones at the cognate sites [126]. HDA19 with MSI1 (MULTICOPY SUPPRESSOR OF IRA1) regulates ABA signalling through H3K9 deacetylation-mediated suppression of ABA receptor encoding genes PYL1, PYL4, PYL5, and PYL6 (PYRABACTIN RESISTANCE 1 (PYR1)-LIKE 1/4/5/6) in Arabidopsis [127]. The Arabidopsis hda19 mutants showed higher ABA accumulation in young seedlings and acquired greater tolerance against different stresses [128–130]. For instance, the hda19 mutant plants showed salt tolerance phenotype due to upregulation of LEA (LATE EMBRYOGENESIS ABUNDANT) and P5CS1 (D1-PYRROLINE-5-CARBOXYLATE SYNTHASE1) proteins which function in preventing protein aggregation and proline (an osmoprotectant) synthesis, respectively, during exposure of various environmental stresses. However, plants harbouring mutations in other histone deacetylases like hda5, hda14, hda15 and hda18 displayed sensitivity to salt stress [129]. HDA19 is a class I HADC, whereas HDA5, 14, 15 and 18 are class II HDACs belonging to RPD3 family. So, these results suggest that class I HDAC (HDA19) and class II HDACs (HDA5/14/15/18) work differently during salt stress in Arabidopsis. HDA19 and HDA6 may play a redundant role in modulating seed germination and salt stress response and ABA- and salt stress-induced gene expression in Arabidopsis [130]. In Brachypodium, a homolog of HDA19, BdHD1, is important in regulating ABA signalling and drought tolerance mechanism by suppressing the drought-responsive genes via deacetylation of H3K9ac lysine residues [131]. A complex of HDA9 with ABI4 (ABA INSENSITIVE 4) regulates ABA homeostasis through repression of ( +)-ABA 8′-hydroxylase enzyme (involved in ABA catabolic pathways) encoding CYTOCHROME P450 genes CYP707A1 and CYP707A2 expression during drought stress [132]. Another recent study showed that HDA9 and PWR (POWERDRESS) interact with the ABI4 to regulate the ABA signalling and ABA-catabolism pathways in response to ABA and drought [133]. In normal conditions, CYP707A1/2 promotes inactivation of ABA by hydroxylation. During drought stress, the HDA9-PWR-ABI4 histone deacetylase complex suppresses CYP707A1/2 genes and promotes ABA accumulation. [132, 133]. These reports indicate that there is a coordination between HDA9, HDA15 and HDA19 to control ABA signalling at several steps upon stress encounter (Fig. 3; Table 2).

In addition to the model plant Arabidopsis, histone deacetylases have been studied in other plants and trees as well. In common beans, HDA6 is upregulated during cold stress indicating its probable involvement in the abiotic stress tolerance [78]. In transgenic tobacco, overexpression of Populus histone deacetylase, 84KHDA903, increased drought stress responses by upregulating the expression of drought-responsive genes DREB3, DREB4 (DEHYDRATION-RESPONSIVE-ELEMENT-BINDING 3/4), and LEA5 (LATE EMBRYOGENESIS ABUNDANT 5) [134]. The over-expression of PtHDT902 (a plant-specific HD2 gene) activated the expression of GA (Gibberellic acid) biosynthesis-related genes, including ENT-KAURENE OXIDASE (KO), ENT-KAURENOIC ACID HYDROXYLASE (KAO), GIBBERELLIN 20-OXIDASE (GA20ox) [135]. As a result, there was an enhancement in primary root growth in transgenic Arabidopsis and inhibition of adventitious root formation in transgenic Populus. However, on the other hand, overexpression of PtHDT902 suppressed the expression of salt-responsive genes HIGH-AFFINITY K⁺ TRANSPORTER 1 (HKT1) and GALACTINOL SYNTHASE 4 (GOLS4) in the transgenic lines. Thus, PtHDT902 is an interesting example of histone deacetylase that can regulate multiple signalling pathways in different manners. In rice, an RPD3-type histone deacetylase HDA1 interacts with IDS1 (INDETERMINATE SPIKELET1) and TPR1 (TOPLESS-RELATED PROTEIN 1) and suppresses the expression of salt stress-responsive genes such as SOS1 (SALT OVERLY SENSITIVE1) and LEA1 (LATE EMBRYOGENESIS ABUNDANT PROTEIN1) [136]. OsHDA705 is another RPD3-type histone deacetylase that regulates GA and ABA biosynthetic genes during rice seed germination. The overexpression of OsHDA705 in rice decreases ABA level and salt stress resistance during seed germination. However, it enhances osmotic resistance during seedling stage [137]. In maize, heat stress affects growth and reduces crop yield. Heat stress induces ROS (Reactive oxygen species), which leads to programmed cell death (PCD) with modulation of chromatin structure by increasing the acetylation level of H3K9 and H4K5 and decreasing the methylation level of H3K9me2 in maize seedlings. The inhibition of HDACs by TSA causes hyperacetylation of histones and increases the superoxide level (O₂⁻), leading to PCD [138]. Another study also revealed that short-term heat stress induces dynamic alterations in H3K9ac and H3K4me2 levels on the promoter region of upregulated heat stress factor (Hsf) and rRNA genes [139]. These genes accompanied by perturbations of cell membranes and increase in ROS levels in maize seedlings helped to counter the stress. These results indicate that HDACs positively regulate the expression of cold-induced gene ZmDREB1 by histone modification and chromatin conformational changes [140]. In kenaf, there are six histone deacetylase genes HcHDA2, HcHDA6, HcHDA8, HcHDA9, HcHDA19 and HcSRT2 that are differentially expressed during different growth stages and drought and salt stresses suggesting their probable role in the plant development and also in the stress responses [141]. In banana, MaHDA2-MaMYB4 repressor complex is recruited on the promoter of ω − 3 fatty acid desaturase genes MaFAD3-1, MaFAD3-3, MaFAD3-4, and MaFAD3-7 to repress their transcription during cold stress [142] (Fig. 3; Table 2). Thus, modulations of histone acetylation by different HAT and HDAC have a significant effect on the signalling pathways that contribute to the stress responses.

Histone acetylation in crops

Crops fulfil the global demand for food, but different environmental stresses cause yield loss. The progressive climate change is also exerting pressure on the growth and development of plants. So, the development of climate resilience crop may be helpful to secure the food demand for the ever-increasing world population. As explained above in this review, different HATs and HDACs modulate histone acetylation to control growth and stress responses in different plants. In this section, the relevance of histone acetylation modulation in crop plants has been discussed (Fig. 3; Table 1, 2). For example, histone acetyltransferase GCN5 has been shown to promote crown root formation in rice plants to keep them erect [55]. A new-type GNAT-like protein OsglHAT1 has inherent H4 histone acetyltransferase activity and its gene is found in the grain weight quantitative trait loci (QTL) in rice [143]. It positively regulates the expression of PGL2 (6-PHOSPHOGLUCONOLACTONASE 2), which is important for the grain length. The overexpression of OsglHAT1 increases several agronomical traits, including grain length, grain weight, yield, and total biomass. A SIR2-type HDAC in rice, OsSRT1 inhibits carbon metabolic flux (glycolysis pathway) in the developing seedling [144], and also promotes starch accumulation in the developing seeds [46, 47]. Other HDACs, OsHDA1 and OsHDA705 are associated with impeded response to salt stress [136, 137]. On the same note, the histone deacetylase OsHDT701 is also associated with weakened innate immunity in rice [104]. In wheat, histone deacetylases TaHDA6 and TaHDT701 have been found to control the innate immunity during Bgt infection [102, 103]. On the other hand, TaGCN5 induces cuticular wax biosynthesis and Bgt growth [101]. In maize, the histone deacetylase HDA108 controls plant height, leaf development, inflorescence patterning and fertility [145]. Besides, histone acetylation dynamics has been also shown to regulate heat stress tolerance [138, 139]. ZmGCN5 provides salt stress tolerance in maize [107], whereas, the HDACs activates the expression of cold-induced gene ZmDREB1 to ensure cold tolerance [140]. There are few reports which have also explained the impact of histone acetylation modulation on fruit ripening. In banana, MaHDA1 impedes fruit ripening [87], whereas MaHDA6 promotes fruit ripening [88]. Similarly, in tomato, SlHDA3 delays fruit ripening [89], whereas, SlHDT3 promotes the fruit ripening [90]. In papaya, CpHDA3 promotes fruit ripening and softening [91]. Cotton is another important crop where few reports have shown the role of histone deacetylases in cotton fiber development and drought tolerance. Expression of GhHDA5 is increased at the time of cotton fiber initiation and down-regulation of GhHDA5 in RNAi lines reduces the cotton fiber initials due to H3K9 hyper-acetylation of ATG8 (AUTOPHAGY 8) gene promoter leading to its higher expression [38]. This study suggests that HDA5 might control autophagy by the repression of ATG8 gene expression via H3K9 deacetylation during cotton fiber initiation. Furthermore, this study also revealed that the activity of GhHDA5 could be inhibited by an HDAC inhibitor Trichostatin A (TSA). The application of the TSA in the in vitro cultured ovules reduces fiber differentiation suggesting that HDACs are essential for fiber development [38]. GhHDT4D histone deacetylase is required for the drought tolerance in cotton [124]. In rice, OsHDA710 has been found to be important for callus formation from the embryo. It represses the expression of AUXIN RESPONSE FACTOR genes OsARF18 and OsARF22 by deacetylating of H3. A mutation in OsHDA710 (hda710) or inhibition of its activity by TSA affected callus formation [146]. Thus, all these examples from different crop plants suggest that the modulation of histone acetylation status can be used as a strategy to make the plants more stress-resilient and more productive. For this purpose, different HAT and HDAC genes could be targeted by molecular biology and molecular breeding approaches.

Acetylation of non-histone proteins

Non-histone proteins can also serve as substrates for lysine acetylation and subsequent deacetylation. Numerous studies have shown that lysine acetylation of non-histone proteins regulates diverse functions in plants [147–149]. Interestingly, some reports have revealed the role of HATs and HDACs in the lysine acetylation dynamics of non-histone proteins. For instance, HDA6 inhibits the kinase activity of BIN2 (BRASSINOSTEROID-INSENSITIVE 2) through deacetylation to enhance BR (Brassinosteroid) signalling in Arabidopsis [150]. A recent report shows that HDA9 and WRKY53 work in a mutually antagonistic manner to control stress responses. In this case, HDA9 interacts with WRKY53 and suppresses its transcriptional activity through lysine deacetylation. Conversely, WRKY53 also inhibits HDA9 activity [113]. HDA14 (HISTONE DEACETYLASE 14) is a chloroplast localized histone deacetylase which was found to control photosynthesis in Arabidopsis. HDA14 regulates lysine acetylation of RuBisCO activase to control the activation of RuBisCo (RIBULOSE-1,5-BISPHOSPHATE CARBOXYLASE/OXYGENASE) enzyme, which is essential for the photosynthesis [149]. It also deacetylates a non-histone protein α/β-tubulins, which is probably acetylated by a putative histone acetyltransferase ELP3 in the Arabidopsis [151]. Another histone deacetylase, HDA15 modulate COP1 (Constitutive Photomorphogenesis1) activity by lysine deacetylation to regulate the photomorphogenesis [152]. In rice, OsSRT1 represses glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity through deacetylation and inhibits carbon metabolic flux (glycolysis pathway) in the developing seedling [144]. SRT2 was also found to control energy metabolism and metabolite transport through deacetylation of inner membrane protein complexes in Arabidopsis [153]. Thus, all these reports suggest that the HAT and HDAC proteins control metabolic and biological functions by tuning the acetylation status of both histone and non-histone proteins. To understand the details of the functioning of HATs and HDACs in non-histone proteins modifications require comprehensive analyses. A comparative analysis of histone versus non-histone proteins as the substrates will be helpful to understand the broader aspects of the functionality of HATs and HDACs.

Undeciphered modules

1. Being a direct modulator of gene expression, usually, HATs and HDACs are at the end of the signaling cascades. How are the developmental and environmental signals transmitted to HATs and HDACs?

2. There are many uncharacterized HATs and HDACs in plants. What is their biological relevance in plant development and biotic and abiotic stress tolerance mechanisms? Few histone modulators (GCN5, HDA6, HDA9, and HDA19) are widely studied. To properly understand the dynamics of acetylation, the other family members should also be discussed in detail.

3. To fine-tune the critical process of gene transcription, there has to be equilibrium between the functions of HATs and HDACs. Which of the HATs and HDACs function synergistically or antagonistically?

4. What is the other HAT-/HDAC-associated genetic/epigenetic components of broad networks of histone acetylation?

5. What is the underlying mechanism of acetylation and deacetylation of non-histone proteins? Does acetylation of non-histone proteins sync with histone acetylation to control the plant’s development and their adaptation in the adverse condition?

Conclusions and future prospects

Histone acetylation dynamics is a gene regulatory epigenetic mechanism that permits switching between permissive and repressive chromatin by HATs and HDACs upon sensing developmental and environmental cues. Once the respective receptors perceive the cues, the signalling cascades are evoked by hormones, secondary messengers and other signalling molecules. The signalling pathways lead to the expression of HATs and HDACs (Fig. 4) that activate and repress target genes, respectively, to regulate downstream pathways. These alterations in the biochemical pathways ultimately regulate development and stress tolerance in plants (Fig. 4). In the past decade, several studies substantiated that histone acetylation dynamics and other epigenetic modifications are integral parts of the transcription machinery for gene regulation during plant development and their adaptation in adverse conditions. This review summarized the recent findings establishing several HATs and HDACs as epigenetic regulators of physiological and biological processes in different plants (Fig. 3). Both epigenetic regulators control numerous developmental processes, including seedling, leaf, root and flower development, fruit ripening, and aging of plants as well as biotic and abiotic stress responses (Fig. 3). They control these processes by regulating biosynthesis and signalling pathways of different hormones, including Auxin, BRs, ethylene, JA, SA, and ABA. Although the field of epigenetics has been extensively explored, some aspects, especially in plants, are yet to be understood entirely. For instance, in many cases, the underlying mechanisms which cause, maintain and transduce these epigenetic modifications are still elusive. Recent studies have demonstrated that HATs/HDACs act in the multiprotein complexes to regulate different biological processes and stress responses (Table 1, 2). Most studies are focused on the identification of HATs/HDACs protein complexes and their targets. However, shreds of evidence are still lacking regarding the underlying mechanism that helps to sense the developmental and environmental cues that decide their co-factors such as TFs, activator and repressor proteins, and other histone modifiers for the action. The regulatory networks of histone acetylation and crosstalk with other histone modifications essential for the different biological processes are not well explored. Several studies have shown the involvement of different HATs and HDACs in the same biological processes; HDA6 and HDA9 in circadian rhythm and flowering [15, 64], HAM1/2 and HD2C with MRG1/2 in flowering [17, 68] and HDA19 and HD2D in photoperiod- dependent and independent flowering, respectively [70, 71]. However, the relationship and orchestration between them are still unestablished. Studies have shown that HDA9-PWR-HOS15 and HD2C-HOS15 associate in a core complex to repress different sets of genes responsible for development and stress responses [53, 72, 122], but the association of HOS15 with other HDACs is unknown. Although HATs and HDACs are histone acetylation modulating enzymes, recent studies have shown them to act on the non-histone targets as well [144, 149–151, 153]. However, the role of HATs/HDACs in the modification of non-histone proteins has not gained that much attention. A comparative analysis of histone targeted processes and non-histone targeted processes regulated by these HATs/HDACs will be worthwhile to understand the functionality of these enzymes. As discussed above, histone modifications by HATs/HDACs have a prominent impact on crop productivity and yield. So, it is imperative to explore the possibility of targeting specific HATs/HDACs by chemical means or using molecular tools to enhance the yield. The CRISPRa dCas9 strategy may also be deployed to activate or repress target genes of HATs/HDACs that have a role in plant development and stress tolerance. These strategies will ultimately lead to improving the yield and stress resilience in crops.

Fig. 4.

An overview of histone acetylation-mediated epigenetic regulation of developmental processes and stress tolerance in plants. The developmental and environmental stimuli trigger signalling cascade that leads to the expression of HAT and HDAC genes. HATs and HDACs are recruited on the promoters of the target genes with the help of sequence-specific DNA-binding activator (co-activators) and repressor proteins (co-suppressor), respectively. HATs generally activate the target genes by adding an acetyl group on lysine residues of histones, while HDACs repress genes by removing acetyl groups added by the HATs. The products of these target genes constitute different biochemical pathways. Thus, HATs and HDACs affect the biochemical pathways and modulate hormones metabolism, ROS homeostasis, cell wall integrity, and membrane stability. They ultimately control developmental processes and adaptation of plants in different environmental conditions through regulation of stress tolerance mechanisms. RGs regulators, TF transcription factor, RP repressor protein, Ac acetyl group, ROS reactive oxygen species

Author contributions

MP conceived the idea and outlined the review. VK wrote the manuscript and prepare figures and tables, JKT provided extensive revisions to the technical content of the manuscript. All authors have read and approved the final version of the manuscript.

Funding

This work is supported by the J.C. Bose National Fellowship Grant of Department of Science and Technology, Government of India (File No. JCB/2018/000001) and Core Grant of National Institute of Plant Genome Research, New Delhi, India and National Post-Doctoral Fellowship Grant (File No. PDF/2017/000892), Science and Engineering Research Board, New Delhi, Government of India.

Declaration

Conflict of interest

The authors have no conflict of interest to declare.