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. 2020 Feb 1;77(15):2899–2917. doi: 10.1007/s00018-020-03460-8

Epigenetic regulation of centromere function

Charmaine Yan Yu Wong 1, Bernard Chi Hang Lee 1, Karen Wing Yee Yuen 1,
PMCID: PMC11105045  PMID: 32008088

Abstract

The centromere is a specialized region on the chromosome that directs equal chromosome segregation. Centromeres are usually not defined by DNA sequences alone. How centromere formation and function are determined by epigenetics is still not fully understood. Active centromeres are often marked by the presence of centromeric-specific histone H3 variant, centromere protein A (CENP-A). How CENP-A is assembled into the centromeric chromatin during the cell cycle and propagated to the next cell cycle or the next generation to maintain the centromere function has been intensively investigated. In this review, we summarize current understanding of how post-translational modifications of CENP-A and other centromere proteins, centromeric and pericentric histone modifications, non-coding transcription and transcripts contribute to centromere function, and discuss their intricate relationships and potential feedback mechanisms.

Keywords: Centromere, Post-translational modifications, Histone modifications, Non-coding transcription, Centromeric transcript, Pericentric heterochromatin

Introduction

The centromere is a specialized region on the chromosome, where kinetochore proteins assemble into a complex that mediates chromosome attachment to microtubules. Centromeres that appear as one primary constriction on the mitotic chromosomes are called monocentromeres, which can be sub-divided into point and regional centromeres. Point centromeres, which are unique for budding yeast species, are short and occupy only one nucleosome [1]. Regional centromeres occupy a larger domain, but have widely variable sizes among humans, mice, chickens, frogs, fruit flies and fission yeast. Some algae, plants, insects and nematodes contain polycentromeres that have multiple primary constrictions or even holocentromeres that occupy the entire poleward faces of the chromosomes. In this review, most studies described were carried out in regional centromeres; while, a few examples from other centromere organizations were used for comparisons.

Centromeric DNA is the DNA sequence where canonical, endogenous centromeres form on. Centromeric DNA sequences are drastically different among species, despite having certain common characteristics (See [2] for an overview of the centromeric sequence diversity). Centromeric DNA of regional centromeres is flanked by highly condensed chromatin domains, which are called pericentric heterochromatin, that facilitate sister chromatid cohesion [37]. Both centromeric and heterochromatic DNA in regional centromeres consist of repetitive sequences. For example, in humans, arrays of α-satellite sequences constitute both the centromeric (mainly High Order Repeat (HOR) arrays) and pericentric regions (mainly monomeric α-satellites) (See [8] for a comprehensive discussion on human centromere sequences). In mice, the minor satellite DNA and the major satellite DNA form the centromere and pericentric heterochromatin, respectively.

In budding yeast species, point centromeres are originally thought to be mainly DNA sequence dependent. In organisms with regional centromeres, forming a centromere does not always require the exact endogenous centromeric DNA sequence, and having the centromeric DNA sequences does not always guarantee the formation of centromeres. Occasionally centromeres are found to reposition to regions outside of the canonical centromeric DNA, and the resulting functional, ectopic centromeres are referred to as neocentromeres. Cases of neocentromeres have been reported in human patients, who have lost the original centromeric sequences, or who have undergone centromere inactivation with their α-satellite DNA remaining intact on their chromosomes [9, 10] (See [11] for more clinical cases of human neocentromeres). On the other hand, in human patients with a dicentric chromosome, which can arise from fusion of chromosome fragments, either one of the two centromeres can become inactivated and the other can function as a monocentric chromosomes [12]. Neocentromeres have also been observed or induced experimentally in different organisms, e.g., by selecting for surviving cells after removing the original centromere [13] (See [14] for a comprehensive review of neocentromeres). The above examples suggest that centromere activity can be established or abolished epigenetically.

Most functional centromeres are marked by a centromeric-specific histone H3 variant centromere protein A (CENP-A) [12]. CENP-A plays a critical role in centromere specification, centromere maintenance and kinetochore assembly. CENP-A and the other constitutive centromere-associated network (CCAN) components, including CENP-C and CENP-T, are required for recruitment of the other kinetochore proteins, including the KMN network (the KNL-1, MIS-12 and NDC-80 complexes) [15]. Studies in human and fly regional centromeres showed that CENP-A is interspaced with H3. Like other canonical histones, CENP-A is diluted in half during DNA replication. However, unlike other canonical histones, which are often replenished in S phase, CENP-A replenishment is independent of DNA replication, though it also occurs only once every cell cycle at various times among organisms [16]. On the other hand, in budding yeast with point monocentromeres and in the nematode Caenorhabditis elegans with holocentromeres, all or most CENP-A on chromatin is turned over during each cell cycle [17, 18].

The molecular mechanism of recruiting new CENP-A to the correct position on the chromosome, and hence maintaining the centromere through cell cycles and generations has become clearer in the last decade [19]. In general, replenishment of new CENP-A at centromere involves licensing, deposition and stabilization. First, the original centromere position is primed by licensing factors, e.g., Mis18 complex (Mis18α, Mis18β, and Mis18BP1/KNL-2) in human cells [20], before CENP-A loading. Second, pre-nucleosomal CENP-A is deposited onto the primed centromeric chromatin, assisted by the CENP-A chaperone, which is HJURP in humans [21, 22], Scm3 in budding yeast and fission yeast [23, 24], CAL1 in Drosophila [25], and potentially RbAp46/48p55/LIN−53 in Drosophila and C. elegans [26, 27]. The CENP-A assembly by HJURP induced the removal of Mis18BP1 from human centromeres [28]. S. pombe RbAp46/48Mis16 binds to CENP-ACnp−1-H4 tetramer and Scm3, and then forms a complex with Mis18 [29]. Third, CENP-A-containing chromatin is stabilized by a maturation process, e.g., CENP-A monoubiquitination in Drosophila [30], or else CENP-A would be removed from the chromatin [3133].

Besides the centromeric epigenetic marker CENP-A, there are multiple epigenetic mechanisms to regulate centromere activity. In this review, we summarize the current knowledge of epigenetic regulations on centromere function, focusing on post-translational modifications on CENP-A, histones, other centromeric and kinetochore proteins, the transcription process and the corresponding transcripts at centromeric and pericentric regions. We discuss the relationships and interdependencies of these epigenetic regulations, their feedback regulatory mechanisms and evolutionary origins.

Post-translational modifications (PTMs) of CENP-A

In the past decade, various post-translational modifications of CENP-A have been identified by mass spectrometry and characterized (Fig. 1 and Table 1). These modifications include methylation, acetylation, ubiquitination, and sumoylation. Modifications on CENP-A are dynamic during the cell cycle and contribute to CENP-A’s localization and function.

Fig. 1.

Fig. 1

Alignment of CENP-A proteins in humans, budding yeast, and maize with histone H3 in humans to show the position of CENP-A post-translational modifications listed in Table 1. The multiple protein sequences are aligned in unipro UGENE (ClustalW). The amino acid sequences are extracted from NCBI: CENP-A isoform a [Homo sapiens]|NP_001800.1; CSE-4 [Saccharomyces cerevisiae]|NP_012875.2; centromeric histone H3 (CenH3) [Zea mays]|NP_001105520.1; histone H3.1 [Homo sapiens]|NP_003522.1. The region of CENP-A targeting domain (CATD) was adopted from [163], which is the loop-1 and alpha helix 2 of the CENP-A histone-fold domain. The region of histone-fold domain of CSE-4 was adopted from [164]. The histone modifications are labeled with the position number followed by the type of modification (green box: methylation; blue box: phosphorylation; beige box: acetylation or ubiquitination)

Table 1.

Post-translational modifications of centromere proteins and their functions

Protein Modification Responsible enzyme Species Function Reference
CENP-A Phosphorylations
 Serine 7 phosphorylation Aurora A/B Humans Is required for cytokinesis completion and correct Aurora B, 14–3-3, PP1γ1, and CENP-C localization [54, 5658]
Non-phosphorylable mutant can bind centromere, does not affect CENP-C localization, nor long-term survival [59]
 Serine 16/18 phosphorylation ? Humans Compacts CENP-A nucleosomal array [51]
 Serine 18 phosphorylation CDK2 Humans Inhibits CENP-A localization to centromere [35]
 Serine 68 phosphorylation CDK1 Humans Inhibits HJURP association and CENP-A premature loading [36, 38]
Expression of non-phosphorylable mutant can rescue CENP-A null cells [39]
 Serine 50 phosphorylation ? Maize ? [60]
Methylations
 Glycine 1 tri-methylation RCC1? Humans Interacts with DNA [51, 61]
 Lysine 124 monomethylation ? Humans ? [50, 60]
 Arginine 37 methylation ? Budding yeast Recruits inner and linker kinetochore proteins [42, 61]
Ubiquitinations
 Lysine 124 ubiquitination CUL4A-RBX1-COPS8 Humans Localizes to centromere [30, 47]
 Polyubiquitination Psh1 or Slx5 Budding yeast Targets CENP-A for proteolysis [42, 43, 51]
Monoubiquitination CUL3/ RDX Fruit flies Stabilizes CENP-A [30, 51]
Others
 Lysine 124 acetylation HAT p300? Humans Increases nucleosome accessibility to chromatin remodelers and disrupts C-terminal binding to CENP-C [49, 50]
 Sumoylation Siz1/Siz2 Budding Yeast Primes CENP-A for polyubiquitination-related degradation [42, 50]
HJURP  Serine 412, 448 and 473 phosphorylation CDK1 Humans Weakens interaction with M18β [62, 63]
M18BP1  Serine/threonine 24 phosphorylation CDK1/2 Humans Prevents premature CENP-A loading [64]
 Threonine 40 & serine 110 phosphorylation CDK1 Humans Prevents M18α:Mis18β binding [65]
 Threonine 653 phosphorylation CDK1/2 Humans Inhibits Mis18BP1 centromere localization [28]
 Phosphorylation ? (Not CDK1/2) Xenopus Inhibits Mis18BP1 interaction with CENP-A in metaphase [68]
Mis18 complex Phosphorylation Plk1 Humans Localizes Mis18 complex and loads CENP-A [67]

Proper timing of CENP-A deposition

CENP-A is loaded in late mitosis to G1 phase in vertebrates [34]. The cell cycle-dependent phosphorylation state of CENP-A is proposed to be critical for timely CENP-A deposition. Human CENP-A serine 18 (S18) is phosphorylated by Cyclin E1/CDK2 from G1 to S phase [35] and serine 68 is phosphorylated by CDK1 in early mitosis [36]. Both phosphorylations at CENP-A S18 and S68 prevent CENP-A’s premature recognition by HJURP and CENP-A loading onto the centromere [35, 36]. Overexpressed phosphomimicking S68E CENP-A cannot associate with HJURP; whereas, overexpressed non-phosphorylatable S68A CENP-A can associate with HJURP, but it is occasionally mislocalized to non-centromeric regions [3638]. On the other hand, LacI-fused non-phosphorylatable S68Q CENP-A has reduced HJURP recruitment to the lacO array at an ectopic site outside the context of the centromere, as compared to wild-type CENP-A [39]. Non-phosphorylatable S68Q CENP-A mutant can localize to centromeres, and expression of this mutant by retrovirus at endogenous level can rescue cell lethality of CENP-A-null cells, suggesting that S68 phosphorylation is dispensable for centromere maintenance [39]. During mitotic exit, CENP-A S68 is dephosphorylated by Protein Phosphatase 1 alpha (PPla), so that CENP-A can be loaded onto the centromere [36]. Drosophila and Xenopus also load CENP-A at late mitosis to G1 phase, using similar temporal regulation by phosphorylation [40, 41]. Further studies are needed to determine whether phosphorylations also control the CENP-A loading time outside of late mitosis to G1 phase in other species (e.g., budding yeast CENP-ACse-4 loading occurs in S phase [17]), and in species that have complete CENP-A turnover every cell cycle.

Eliminating mislocalized CENP-A

Ubiquitination of CENP-A helps to further ensure that CENP-A’s distribution is exclusively on the existing centromeres in budding yeast and Drosophila. In budding yeast, ectopically localized CENP-ACse4 is first subjected to sumoylation by E3 ligases Siz1 and Siz2, followed by polyubiquitination mediated by E3 ubiquitin ligase Slx5, and it is then targeted for proteolysis [42]. When CENP-ACse4 is overexpressed, another budding yeast E3 ubiquitin ligase, Psh1, polyubiquitinates mislocalized CENP-ACse4 [43]. The presence of CENP-ACse4 chaperone Scm3 reduces CENP-ACse4 ubiquitination by Psh1 in vitro, suggesting that Scm3 protects CENP-ACse4 from degradation [44]. In Drosophila, E3 ubiquitin ligase SCFPpa destabilizes CENP-ACID and regulates CENP-ACID chromatin localization [45]. A recent study in human cells revealed that CENP-A can localize to chromosome arm regions that are transcriptionally active before S phase [46]. CENP-A not bound by CENP-C is stripped off from the nucleosome when the DNA is replicated [46]. Whether CENP-A ubiquitination and the DNA replication machinery coordinate to evict CENP-A is not clear.

Effects on CENP-A nucleosomal structure

While polyubiquitination removes ectopically loaded CENP-A, monoubiquitination is found to stabilize CENP-A on the centromere in Drosophila and human cells [30, 47]. In Drosophila, CENP-ACID is stabilized by E3 ligase CUL3/RDX-mediated monoubiquitination in a CAL1-dependent manner, potentially when CAL-1 forms a pre-nucleosomal complex with CENP-ACID during mitosis [30]. In humans, CENP-A monoubiquitination on the highly conserved lysine 124 (K124) residue by E3 ligase CUL4A-RBX1/ROC1 promotes CENP-A dimerization, increases CENP-A’s affinity to HJURP, and is required both for the maintenance of old CENP-A and the recruitment of newly synthesized CENP-A [47]. However, in another study, the CENP-A K124R mutant is still competent for centromere maintenance [39, 47, 48]. Ubiquitination on additional residues on CENP-A might also be involved in maintaining CENP-A stability.

Interestingly, different modifications can be found on human CENP-A lysine 124. CENP-A K124 acetylation, which tightens the histone core, was suggested to mediate nucleosome sliding and increase centromere accessibility before DNA replication [49, 50]. In early S phase, CENP-A K124 was found to be monomethylated, which is proposed to avoid over-replication of centromeric DNA [50]. Therefore, even the same residue, e.g., K124, on CENP-A can undergo modification transitions to tailor for specific functions at different cell cycle stages, adding complexity to epigenetic regulations by PTMs.

Several other post-translational modifications on human CENP-A were also implicated in directly affecting CENP-A nucleosomal structure. For instance, CENP-A glycine 1 tri-methylation was suggested to aid the interaction of CENP-A with the underlying α-satellite centromeric DNA, and serine 16 and 18 phosphorylations are proposed to form a local secondary salt bridge structure that compacts the CENP-A nucleosomal array [51].

Localization of other kinetochore proteins and mitotic progression

One of the main functions of CENP-A is recruiting kinetochore proteins to the centromere. The kinetochore recruitment requires both CENP-A targeting domain (CATD) and either the carboxyl- or amino-terminal tail of the CENP-A protein in humans. H3 chimeras containing the CENP-A CATD domain, with either CENP-A amino-terminal tail (residues 1–29) or carboxyl-terminal tail (residues 135–140), were sufficient to recruit and maintain kinetochore proteins on human endogenous centromeres or on neocentromeres [52, 53]. This result suggested that kinetochore proteins are redundantly recruited and maintained by the tails of CENP-A together with the CENP-A CATD domain. For the short CENP-A carboxyl-terminal tail outside the conserved histone-fold domain, no specific post-translational modification has been reported to date. CENP-A amino-terminal tail deletion causes serious mitotic defect, but this can be rescued when CENP-A amino-terminal tail is substituted with that of H3, which is also phosphorylatable [54]. At the amino-terminal tail, phosphorylation of human CENP-A serine 7 by Aurora A and Aurora B appears in prophase, peaks in metaphase, and levels off in anaphase [55, 56]. Overexpression of serine 7 non-phosphorylatable CENP-A mutant has been shown to cause chromosome misalignment at metaphase [56], sister chromatid cohesion defects [57], reduced localization of CENP-C [54] and a phospho-binding protein, 14–3–3, from the centromere [54], dispersed Aurora B localization away from the inner centromere to chromosome arms in prometaphase [56, 57], and dispersed PP1γ1 from the midbody to the anaphase chromatids as well [58]. Moreover, overexpression of serine 7 phosphomimicking CENP-A mutant has abolished PP1γ1 localization at the midbody in anaphase [58]. CENP-A phosphorylated at serine 7 has been shown to bind 14–3–3, which is proposed to bridge CENP-A to CENP-C [54]. However, the importance of S7p remains elusive as a recent study using auxin-induced degradation (AID) and gene editing system revealed the opposite result, in which cells with only S7A CENP-A mutant do not display any abnormalities in centromere function, including CENP-C recruitment, nor long-term survival defects [59]. Barra et al. attributed the previous reported S7A defects to having a suboptimal level of CENP-A [59]. In maize, serine 50 phosphorylation of CENP-A has a similar kinetics as CENP-A S7 phosphorylation in humans, with a sharp reduction at metaphase–anaphase transition, but the function of S50 in maize is not well understood [60]. Moreover, budding yeast CENP-ACse4 methylation at arginine 37 may be involved kinetochore recruitment and centromere function, as the absence of this methylation (Cse4-R37A mutant) results in slightly reduced levels of kinetochore proteins (Mtw1 and Ame1) on the centromere in cbf1 deletion background [61]. Cse4-R37A mutant also results in an increased plasmid loss rate in cells with plasmid lacking CDEI element, and synthetic lethality or growth defect when combined with COMA (Ctf19-Okp1-Mcm21-Ame1) mutants or cbf1 mutant [61].

Post-translational modifications on other proteins important for CENP-A centromere targeting

Many proteins involved in the CENP-A chromatin assembly process are also post-translationally modified (Table 1). CENP-A chaperone HJURP serine 412, 448 and 473 phosphorylations by CDK1 weaken the interaction between HJURP and Mis18β [62], and a non-phosphorylatable HJURP mutant precociously deposits CENP-A on to the centromere [63]. CDK1 and CDK2 also phosphorylate the centromere licensing factor Mis18BP1 to suppress its centromere localization during S, G2, and M phase [64]. Phosphorylation of Mis18BP1 at T653 prevents premature centromere targeting at G2 [28]. Phosphorylation of Mis18BP1 at T40 and S110 reduces its affinity to Mis18α and Mis18β, and a phosphomimicking mutant prevents new CENP-A recruitment [65, 66]. The inhibition of HJURP and Mis18BP1 localization to centromere in turns restricts the centromere licensing time to late mitosis or early G1, and prevents premature CENP-A chromatin assembly. In contrast, Polo-like Kinase 1 (PLK1) phosphorylates human Mis18 complex to promote its centromere localization in early G1, contributing to CENP-A deposition [67]. Taking these results together, CENP-A deposition, at least in humans, is likely to be controlled by integrated phosphorylation and dephosphorylation signals from CDK1, CDK2 and PLK1. In Xenopus, phosphorylation of Mis18BP1 also inhibit its association with CENP-A nucleosomes during metaphase, but this phosphorylation is independent of CDK [68]. It is worth to note that many of the above findings are yielded from organisms like humans and Drosophila, which have their CENP-A loaded in late G1 or anaphase [34, 40]. As the loading time of CENP-A varies among species, it will be interesting to further investigate whether the CENP-A loading mechanisms, as well as their regulations, are conserved in different species.

Histone modifications important for centromere function

Centromeric and pericentromeric histones H3 and H4 acetylation status

Many centromeric histone modifications have been identified as pertinent to centromere functions (Table 2). Histone acetylation, as commonly found at actively transcribed regions in euchromatin, neutralizes the positive charge in histones, weakening histone–DNA interactions, thereby opening up the chromatin [69]. One of the earliest studies in barley has shown that centromeric histones H3/H4 are hypoacetylated in mitosis [70]. In fission yeast, centromeric histones H3/H4 are maintained in hypoacetylated states by RbAp46/48Mis16 and Mis18 [20]. In budding yeast, H4 in the CENP-ACse4 nucleosome is hypoacetylated at K16 by Sir2, and this hypoacetylation is required to maintain kinetochore integrity and accurate chromosome segregation [71]. In humans and Drosophila, the repetitive centromeric chromatin also contains hypoacetylated H3/H4 [3]. The general hypoacetylated state at the centromere is consistent with the cytological observation that the centromeres are the more condensed part of the chromosomes.

Table 2.

Histone modifications of centromeric core chromatin and pericentric heterochromatin

Location Modifications Function Species Reference
Centromeric and Pericentromeric H3/H4 hypoacetylation Promotes condensation of centromeric chromatin in barley; maintains kinetochore integrity and accurate chromosome segregation in budding yeast Barley, fission yeast, budding yeast, humans, Drosophila [3, 20, 70, 71]
Centromeric H3 lysine 4 di-methylation Targets HJURP to the centromere and maintains kinetochore Humans, Drosophila, Arabidopsis, fission yeast, chicken, rice [6, 73, 78, 79, 83]
H3 lysine 9 di- or tri-methylation ? Rice, chicken [6, 87]
H3 lysine 27 tri-methylation ? C. elegans [18]
H3 threonine 3 phosphorylation Recruits CPC via Survivin binding and important for Aurora B function Fission Yeast [90, 92, 93]
H2A serine 121/ threonine 120 or 133 phosphorylation Localizes CPC component Shugoshin to centromere in fission yeast Fission yeast, maize, wheat, rice, barley, L. elegans, humans [91, 9497]
H4 acetylation Primes the centromere prior to CENP-A deposition in humans Rice, humans [73, 74]
H4 lysine 5 and 12 acetylations Are required for CENP-A deposition Chicken [72]
H4 lysine 20 monomethylation Is required for CENP-T binding Humans, chicken [88]
Pericentric H3 lysine 9 di or tri-methylation Is crucial for mitotic progression, sister chromatids cohesion, and kinetochore–microtubules interaction; Is required for heterochromatin formation (see Table 4) Humans, Drosophila, Arabidopsis, fission yeast, maize [3, 4, 7982, 84, 85, 149, 164, 166]

On the other hand, H4 lysine 5 and lysine 12 acetylations, which were dependent on RbAp48-HAT1 complex but not Mis18, were found to be enriched in non-repetitive centromeres in chicken DT40 cells [72]. Consistently, H4 acetylations (at lysine 5, 8, 12, and 16) were found in rice centromeres where active genes are present [73]. H4 acetylation mediated by the human Mis18 complex was suggested to prime or license the centromere prior to CENP-A deposition [74]. A study in barley has shown that centromeric H4 lysine 5 acetylation is dynamic across the cell cycle, in which H4 lysine 5 deacetylation in metaphase is proposed to promote condensation of centromeric chromatin [75] (See [76, 77] for reviews focusing on the dynamics of histone modifications).

Histone modifications at centromeric core versus pericentric heterochromatin

As mentioned in the introduction, CENP-A-containing centromeric core in regional centromeres is usually flanked by pericentric heterochromatin. Multiple approaches, including high-resolution imaging of stained chromatin fibers, pull-down of nucleosome using CENP-A antibody, and chromatin immunoprecipitation (chIP), have allowed us to distinguish the centromeric (CEN) chromatin from the pericentric heterochromatin by having distinct histone modification patterns. For example, in humans and Drosophila, while their CEN chromatin contains H3 lysine 4 dimethylation (H3K4me2), the pericentric heterochromatin consists of H3 lysine 9 di- or trimethylation (H3K9me2 or H3K9me3) [3, 78]. These modification patterns are consistently reported in other model organisms like the flowering plant Arabidopsis thaliana, fission yeast and maize [7982]. A study in human artificial chromosomes (HACs) has demonstrated that H3K4me2 is required for targeting HJURP to the centromere and for kinetochore maintenance [83]. Mitotic-specific H3K9me3 at pericentric heterochromatin is crucial for mitotic progression and kinetochore–microtubule interaction in human cells [84, 85]. However, such distinct centromeric and pericentric histone modification pattern seems to be less obvious in chicken. In chicken DT40 cells, in which the centromeric chromatin are also mostly repetitive, H3K9me3 was robustly observed flanking the CENP-A subdomains on stretched chromatin fibers, but only low levels of H3K4me2 were detected in CEN chromatin by super-resolution microscopy [6]. Despite the difference in H3K9me3 pattern in human and chicken DT40 pericentric chromatin, one similarity among them is histone H4 lysine 20 monomethylation (H4K20me1) in CENP-A nucleosomes. H4K20me1 is usually associated with active transcription and is required for kinetochore assembly, probably through CENP-T binding [88, 89].

While H3K9me3 is enriched on chicken DT40 repetitive centromeres, it is not enriched on non-repetitive centromeres (Chromosome 5, 27 and Z) or neocentromeres [13]. In fact, the absence of H3K9me3 at non-repetitive neocentromeres has also been reported in a human cell line IMS13q [86]. On the other hand, on centromere 8 (Cen8) in rice, which contains a low abundance of highly repetitive satellite DNA, CENP-A centromeric chromatin is embedded in a larger H3K9me2 region [73, 87]. This whole H3K9me2 region, including CENP-A chromatin, is low in H3K4me2 [87], which is different from that in humans, flies and HACs.

Other than methylations, histone phosphorylations have also been reported. In maize, H3 serine 28 phosphorylation (H3S28P) occurs at pericentric chromatin from prometaphase to anaphase, and is proposed to function in sister chromatid cohesion [60]. In fission yeast pericentric chromatin, mitotic histone kinase Haspin phosphorylates H3 threonine 3 (H3T3P) [90], while spindle checkpoint kinase Bub1 phosphorylates H2A serine 121 (H2AS121P) [91]. These two phosphorylations are important for recruiting components in the chromosomal passenger complex (CPC), including Aurora B, and the cohesin protector, Shugoshin, to mediate sister chromatid bi-orientation and cohesion [92, 93]. In humans, the corresponding modification of H2AS121P is H2A threonine 120 phosphorylation (H2AT120P), which is also recognized by Shugoshin at the pericentric heterochromatin [94]. The corresponding phosphorylation in other plant species is either H2AT120P or H2AT133P [9597]. In barley and Luzula elegans, H2AT120P is present on the centromeres, with a gap in between the sister chromatids, as shown by structured illumination microscopy [97]. Despite its different distribution and unclear function in cohesion in plants, this H2A modification represents a common epigenetic mark for centromeric chromatin in both monocentric (e.g., tomato, barley, rye, tobacco) and holocentric plant species (e.g., L. luzuloides and L. elegans)[96].

For the nematode C. elegans, which also have holocentromeres, CENP-AHCP−3 domains are positively correlated (r = 0.64) with heterochromatin mark H3K27me2/3, and negatively correlated (r = − 0.6) with actively transcribed mark H3K36me3, but the causal relationships between these histone modifications and CENP-AHCP-3 localization and their functions on the centromeres are not clear [18]. Taken together, some histone modification patterns at centromeric chromatin and pericentric heterochromatin are conserved among organisms, while some are unique. Their exact roles in specific species deserve further investigation.

Centromeric transcription

As a constricted region on the mitotic chromosome bound by kinetochores [98], the centromere was first conceived to have minimal transcriptional activity. Surprisingly, as opposed to this early speculation, transcription at the centromere is found to be compatible with centromere’s function in many species.

Centromeric transcripts as a structural and regulatory component for the centromere

Transcripts from the centromere have been detected, and are found to be required for centromere function in budding yeast [99, 100], fission yeast [101, 102], mammals [103, 104], insects [105, 106] and plants [73, 107]. The centromere-derived RNAs found in different organisms are heterogeneous in terms of their size, stability and the cell cycle timing in which they are transcribed (Table 3). RNAs originated from centromere can be as short as 21–23 nt for short interfering (si)RNAs in fission yeast, or over 5 kb for long non-coding (lnc) RNAs in humans [100, 105, 107, 108]. (See [109, 110] for reviews on the classifications of centromeric transcripts and their potential functions).

Table 3.

Organisms with known CENP-A containing centromeric transcription and its function

Species Transcription site Enzyme RNA Class Centromeric function or characteristic of the RNA Reference
Budding Yeast (Saccharomy-ces cerevisiae) CEN DNA RNAPII  > 200 nt non-coding RNA Optimal expression level is required to maintain minichromosome stability and centromeric protein levels [99, 100]
Fission Yeast (Schizosacch-aromyces pombe) Central domain RNAPII & Chd1  ~ 0.5 kb non-coding RNA Highly turnovered centromeric transcripts were detected in exosome mutants or centromeric protein mutants [167]
Maize (Zea mays) Centromeric CRM and CentC repeats ? 40–200 nt single stranded RNA Associates tightly with the kinetochore [107]
Promotes CENP-C localization to the kinetochore [113]
Beetles (Palorus ratzeburgii) Centromeric PRAT repeats RNAPII 0.5–5 kb non-coding RNA Is highly expressed and found in nucleus but function unknown [105]
Fruit fly (Drosophila melanogaster) Chromosome X centromeric Satellite III repeats RNAPII & FACT - Is required for CENP-A loading [106, 124]
0.36–1.3 kb long non-coding RNA Is required for CENP-A, CENP-C and kinetochore proteins localization, proper chromosome segregation and male-specific lethal complex localization
Mouse (Mus musculus) Minor satellites (Centromeric core) ? 200–400 nt non-coding RNA Associates with CENP-A chromatin, Aurora B and Survivin in CPC and is required for Aurora B activity [103, 114]
120 nt non-coding RNA Forced accumulation leads to chromosome missegregation and loss of sister-chromatid cohesion and mislocalizes Aurora B centromeric localization [103, 114]
Tammar wallaby (Macropus eugenii) Centromere-enriched retroelements (LINE, SINE, transposons) ? 35–42 nt Crasi RNA Localizes to the centromere; ssRNAs and dsRNAs are required for CENP-B localization [167]
Human (Homo sapiens) Centromeric α-satellites RNAPII - High level transcription inhibits kinetochore formation in HAC [141]
1.3 kb non-coding RNA Interacts with CPC, CCAN components: INCENP and Aurora B [104]
RNA knockdown increases Aurora B activity [104]
Is required for centromeric CENP-C, INCENP and Survivin loading and nucleolus CENP-C and INCENP targeting [112]
Frog (Xenopus laevis) Frog Centromeric Repeat 1 ? 170 nt non-coding RNA Associates with half of the centromeres and is required for normal Aurora-B localization to the inner centromere [115]

Centromeric ncRNAs may serve a structural or scaffolding role in the assembly of the kinetochore complex or in centromere targeting (Fig. 2d). The lncRNAs were found to associate with soluble HJURP and CENP-A, and the association is required for CENP-A centromere targeting [108]. A recent study also revealed that the α-satellite lncRNAs are cis-acting [111]. On the other hand, human centromeric RNAs have been found to bind and keep kinetochore proteins in the nucleolus [112]. The authors proposed that centromeric RNAs facilitate the preassembly of kinetochore proteins at the nucleolus, prior to their localization at the centromere. Centromeric RNAs’ structural role is likely conserved in other species. Maize centromeric ncRNAs co-precipitated with CENP-A chromatin [107]. CENP-C requires centromeric ncRNAs for its localization to maize, Drosophila and human centromeres [106, 112, 113].

Fig. 2.

Fig. 2

Proposed mechanisms of centromere regulation via transcription. (Top) Transcription process is proposed to introduce chromatin modifications by opening up chromatin, facilitating chromatin modifiers binding, and promoting histone exchange. a Centromeric RNAPII is associated with different stalling factors (see table), which may maintain an open chromatin state. b FACT is found on the centromere in human, chicken DT40 cells, and Drosophila [122124]. In DT-40 cells, chromatin remodeling factor CHD1 is associated with FACT [123]. In Drosophila, FACT is required for new CENP-ACID loading [124]. In budding yeast, CENP-A degradation by E3 ubiquitin ligase requires FACT [126]. In fission yeast, FACT represses ectopic CENP-A localization [125]. c Histone exchange during transcription process is proposed to deposit new CENP-A or to remove ectopic CENP-A. Human transcription coupled H3.3 chaperone ATRX/DAXX is associated with ectopic centromere in human cancer cells [135]. (Bottom) Transcripts originated from centromeric or non-centromeric region have different forms and diverse effects in different organisms. d Long or short non-coding RNAs at the centromere are required for the targeting of some centromeric proteins (see table). e Centromere transcripts help to modulate Aurora B activity. The Aurora B kinase activity is promoted by cenRNAs in mouse and frog [114, 115], and is suppressed by cenRNAs in human cells [104]. f Non-coding RNAs are processed into short interfering RNAs (siRNAs) by the RNAi silencing complex (RISC), which can guide Argonaute binding onto the nascent transcript. In fission yeast, the AGO-1 RNAi machinery is involved in the recruitment of histone methyltransferase Clr4 for H3K9 methylation. H3K9me3 is then recognized by HP1 homolog, Swi6 [139, 149152]. Swi6 is important in establishing pericentric heterochromatin and facilitating initial CENP-ACnp1 establishment in de novo centromeres. (G) In nematodes, the active transcribed regions are anti-correlated with the CENP-AHCP-3 localization [18]. CSR-1 RNAi pathway produces 22G-RNAs from germline mRNAs [160], which may facilitate chromatin modifications and inhibit HCP-3 binding. Related sections are highlighted for detailed descriptions and references

Centromeric non-coding RNAs may also serve a regulatory role in the activity of Aurora B kinase in CPC (Fig. 2e). Human α-satellite RNAs suppress Aurora B’s kinase activity [104]. In contrast, mouse minor satellite RNAs and Xenopus egg extracts’ centromeric non-coding transcripts fcr1 are required for Aurora B’s kinase activity [114, 115]. Despite the observed opposing effects on Aurora B function, knockdown of centromeric RNAs in humans, mice and Xenopus all leads to improper spindle attachments and chromosome missegregation [103, 104, 116]. Yet, further investigations are needed to reveal the exact role of centromeric RNAs in regulating centromeric protein activity and understand the mechanistic differences among organisms.

Transcription-coupled chromatin modifications

In line with the discovery of centromere transcripts, the process of transcription itself may have a role in centromere function. According to the characterization of the promoter sequence, the 5′ cap structure and the 3′ poly-A tail of the centromeric and pericentric RNAs, RNAPII is found to be responsible for their production in fission and budding yeast, beetles, and humans [99, 105, 117120]. In humans, Bub1 recruits RNAPII to the centromeres, and the resulting transcription is important for the accumulation of Shugoshin [94]. Elongating RNAPII (phosphorylated at Ser2), RNAPII-specific transcription factor Carboxyl-terminal domain phosphatase 1 (CTDP1), and a FACT subunit Structure Specific Recognition Protein (SSRP1) are found to localize at the centromere on human mitotic chromosomes [119, 121]. RNAPII inhibition by α-amanitin reduces centromeric transcription and compromises kinetochore function in humans and beetles [105, 119]. Nonetheless, how RNAPII transcription functions at the centromere remains obscure. Potentially, RNAPII may serve as a platform to recruit chromatin modifiers, or stall to shape the chromatin environment (Fig. 2a). Alternatively, transcriptionally compatible chromatin may promote histone exchange by associating with the corresponding histone chaperones to facilitate CENP-A loading.

FACT associated with RNAPII was shown to facilitate centromere protein recruitment. FACT binds to the histone-fold domain of CENP-W directly, and stimulates CENP-T/W complex deposition at the centromere region in human cells [122] (Fig. 2b). In chicken DT40 cells, CENP-H recruits SSRP1 and its interacting chromatin remodeling factor CHD1 to the centromeres, which together facilitates the deposition of new CENP-A [123]. In Drosophila, FACT is recruited by the CENP-ACID chaperone, CAL-1, to promote RNAPII transcription, which destabilizes H3 nucleosomes and facilitates new CENP-ACID loading [124]. In fission yeast, FACT deletion induces the deposition of CENP-ACnp1 onto ectopic sites only, but does not affect CENP-ACnp1 on the endogenous centromeric regions, suggesting that FACT may act by promoting the correct localization of histone H3 in the genome [124, 125]. Consistently, in budding yeast, the degradation of CENP-ACse4 by E3 Ubiquitin ligase Psh1 requires FACT [126].

Evidences suggested that RNAPII may be stalled at centromeres. Depletion of RNAPII transcription restart factor Ubp3 or TFIIS leads to increased CENP-ACnp1 deposition onto fission yeast centromeres, suggesting that restart factors normally restricts CENP-ACnp1 deposition [127]. Potential transcription elongation repressors, including BRCA1, KDM2A, Dicer, and DNMT3B were found to localize to vertebrate centromeres [128131] (Fig. 2a). The retention of RNAPII at the centromere may open up the centromeric DNA and facilitate the recruitment of CENP-A deposition factors or chromatin modifiers.

Transcription-coupled histone exchange is important for the turnover of some histone variants that are replication independent, such as CENP-A [132]. As DNA is being transcribed, histones are temporarily removed and reassembled, providing a chance to reload histones and incorporate specific variants with the help of chaperones that are associated with the RNA polymerase [133]. Centromeric chromatin is proposed to be pre-occupied by histone variant H3.3 after DNA replication and prior to new CENP-A loading [134]. This placeholder, H3.3, is loaded independent of replication, but is coupled to transcription [109, 134]. Besides, ectopic CENP-A domains in human cancer cells are found to be associated with transcription-coupled H3.3 chaperones ATRX/DAXX [135] (Fig. 2c). Whether transcription facilitates the replacement of H3.3 by CENP-A at a specific cell cycle stage remains to be determined.

Regulation of centromeric transcription

The transcription of centromeric RNAs has to be maintained but kept at a low level. At human centromeres, there is transcriptionally permissive mark H3K4me2, but not H3K4me3, which is a strong transcription histone mark [83]. Knocking down histone H3 lysine 4 demethylase KDM5A reduced α-satellite RNAs levels by half and resulted in genomic instability in humans [136]. Moreover, tethering a transcription suppressor to HAC α-satellites destabilizes the HAC, accompanied by a loss of H3K4me2 and a gain of H3K9me3 [83, 137]. This inactivation of HAC centromere can be rescued by p65-induced, H3K9ac-associated transcription [138]. Thus, the centromeric transcription level can be regulated by the landscape of histone modifications on the chromatin. In budding yeast, blocking centromeric transcription by lacI binding to lacOs flanking the centromere resulted in increased minichromosome loss [100]. These studies suggest that a low level of centromeric transcription is favorable for centromere function.

On the other hand, centromere function seems to be incompatible with strong centromeric transcription. Neocentromere formation repressed the expression of nearby genes in fission yeast [139, 140]. Conversely, induced expression of proximal genes repositioned the neocentromere in the yeast Candida albicans [141]. Therefore, the activity of the centromeres and nearby transcription may affect each other. Overexpression of the centromeric transcripts caused by adding a strong promoter [103, 142, 143], tethering a transcriptional activator to the centromere [137, 144], or removal of DNA methylation by DNMT3B depletion [83] also leads to chromosome missegregation. Even for budding yeast centromeres, which are originally thought to be genetically regulated, induced overexpression of centromeric RNAs reduces chromatin association of kinetochore proteins [145]. Overexpression of centromeric RNAs by deletion of centromeric transcription repressor, H2A.ZHtz1 or Cbf1, leads to reduced levels of centromeric CENP-ACse−4, CENP-CMif2 and AuroraBIpl[100]. It was proposed that the overexpressed centromeric RNAs may titrate centromeric proteins away and rendered their mislocalizations [103]. Knocking down centromeric RNAs in htz1 or cbf1 deletion mutant partially rescues minichromosome loss, suggesting a balanced level of centromeric RNAs is needed for centromere function [100]. In addition, centromeric transcript level was found to be up-regulated under stress conditions and in human cancer cells [131, 146]. The accumulation of centromeric transcripts may result from defects in RNA processing by exosome, as some centromeric RNAs, such as those in fission yeast, are known to have a high turnover rate [147, 148].

Transcription at pericentric heterochromatin

Non-coding transcription at the pericentric region remodels the chromatin to form heterochromatin and facilitate gene silencing. In fission yeast, Argonaute-bound, pericentromere-derived siRNAs recruit histone methyltransferase Clr4 to methylate H3 at lysine 9 [139, 149152]. H3K9me in turn is recognized by the heterochromatin protein 1 (HP1) homolog, Swi6, which sets the boundary for pericentric and centromeric regions [81]. The pericentric heterochromatin is required for the initial establishment of CENP-ACnp1 domain, but not for its maintenance in fission yeast [81, 153] (Fig. 2f).

The links between the non-coding transcripts, the RNAi pathway, and heterochromatin formation may be conserved in other organisms. In mouse and chicken–human hybrid DT40 cells, knockdown of an RNAi component has resulted in an accumulation of long transcripts, destabilization of HP1 and reduction of H3K9 methylation at the pericentromere [128, 154, 155]. Pericentric heterochromatin formation is required for CENP-A loading in mice and Drosophila, but is dispensable in chicken–human hybrid cells, C. albicans, and C. elegans, suggesting that heterochromatin is not a universal prerequisite for centromere function [128, 141, 156158, 160]. However, other siRNAs that originate from centromeric or pericentric chromatin may be involved in regulating centromere function (Table 4).

Table 4.

Relationship between transcription, RNAi, heterochromatin assembly and centromere function

Species Transcription site RNAi pathway Heterochromatin function of the transcription/ RNAi or phenotypes in mutant/ overexpression Reference
Fission Yeast (Schizosaccharo-myces pombe) Pericentric outer repeats dg region Ago1 RISC associates with Stc1 to recruit histone methyltransferase Clr4 for H3K9 methylation, H3K9me3 is then recognized by HP1 homolog Swi6, whereas H3K9me2 is important to maintain the siRNAs accumulation. Defective RNAi leads to chromosome missegregation [101, 102, 150, 152, 153, 166, 169]
Transfer RNA alanine gene at the centromeric and pericentric boundary by RNA Pol III - Prevent spreading of heterochromatin [170]
Fruit fly (Drosophila melanogaster) ? Piwi Piwi RNAi pathway is required for heterochromatin silencing and HP1 localization [158, 171]
Chicken DT40-human hybrid cells α-satellites ? Dicer deficient cells mislocalize cohesin Rad21 and Bub1, but do not affect CENP-A and CENP-C [128]
Arabidopsis thaliana 180 bp centromeric satellite repeats ? Dicer mutant abolishes 23–24 nt centromeric small RNAs, but do not affect H3K9me2 nor chromosome segregation [79]
Tammar wallaby (Macropus eugenii) Centromere-specific repetitive satellites ? Crasi RNAs are required for recruiting H3K9me3 at pericentric heterochromatin [168]
Mouse (Mus musculus) Minor satellites (Centromeric core) ? Dicer-null cells inhibit cell proliferation but not histone modification at the pericentromere [154, 155]
Dicer knockdown reduces viability and differentiation ability [155, 156]
Accumulation of 120nt RNAs affect distribution of heterochromatin marks H3K9me and HP1 [103, 155]
Major satellites (Pericentromere) ? Histone methyltransferase Suv39h promotes H3K9me at pericentromere, and is required for viability and chromosome stability [172]
Association of HP1 to pericentromere is RNA-dependent [154]
Human (Homo sapiens) α-satellites AGO2 The AGO2 slicer activity is required for proper chromosome segregation [173, 174]
Association of HP1a to pericentromere is RNA-dependent [174]
Nematode (Caenorhabditis elegans) Germline genes 22G-siRNA CSR-1 Is required for proper chromosome segregation, kinetochore organization and P-granule structure maintenance [160]

Relationship of the centromere with other RNA interference pathways

In holocentric C. elegans, CENP-AHCP−3 domains are inversely correlated with the transcribed regions in the germline, which are loci targeted by antisense 22G-RNAs generated by the Argonaute CSR-1 RNAi pathway [18, 160]. CSR-1 protects its targets from being silenced by other RNAi pathways and optimizes the target transcript levels [161, 164]. Disruption of CSR-1 RNAi pathway leads to chromosome missegregation, which is proposed to be caused by its target expression level changes [160]. However, CSR-1 and 22G-RNAs may potentially also affect CENP-AHCP−3 organization at the chromatin level (Fig. 2g).

Conclusion

Since the identification of CENP-A as a fundamental mark at the centromere, efforts have been made to unravel the mechanism that replenishes CENP-A after DNA replication, and hence maintains the centromere identity in every cell cycle. While many protein factors directly interacting with CENP-A have been identified, the post-translational modifications, chromatin environment, and transcriptional status that regulate precise temporal and spatial centromere assembly and function are just beginning to be understood.

Post-translational modifications of centromeric proteins, centromeric and pericentric histones are involved in governing the centromere function. These modifications can be highly dynamic with respect to the cell cycle phases. Phosphorylation on CENP-A and centromeric proteins often controls their physical interactions and deposition timing. Ubiquitination on CENP-A is crucial for its stability and restricting its localization. Methylations, acetylations and phosphorylations on specific centromeric histone proteins can influence the localization of other centromeric proteins.

While the functions of many histone modifications on the centromere are not completely clear yet, they can regulate centromeric transcription. Non-coding centromeric transcription event has been shown to be essential in several organisms. Most of the centromeric RNAs are transcribed by RNAPII at a tightly controlled, relatively low level. The transcription activity may function to recruit chromatin modifiers for regulating the centromeric chromatin environment, or the centromeric RNAs may function to facilitate kinetochore function as a structural or regulatory component. At the pericentric heterochromatin flanking the centromeric core, transcription, RNAi pathway and specific histone modifications may cooperate to facilitate sister chromatid cohesion, CENP-A loading or centromere establishment. Besides CENP-A, centromeric and pericentric histone modifications and transcription may function as conserved epigenetic mechanisms to create a favorable chromatin environment for centromere specification.

Following the discoveries of post-translational modifications of centromeric proteins, centromeric chromatin and transcriptional environment, future studies are anticipated to reveal more specific molecular functions of these epigenetic factors on centromere function, and the relationships among these different epigenetic pathways. How the centromeric marks are first established and then maintained? An active, functional centromere is likely to be crucial for the inheritance of these epigenetic marks, possibly constructing a positive feedback mechanism. It will be interesting to study how a functional centromere signals and regulates histone modifications and centromeric transcription, and it will be fascinating to understand how chromosomes are accurately transmitted from the beginning of eukaryotic life, via the propagation of epigenetic marks that define the centromere.

Acknowledgements

This work was supported by the General Research Grant [grant numbers 17126717, 17113418] and the Collaborative Research Fund [grant numbers C7058-18G]. We thank our lab members for critical reading and helpful suggestions on the manuscript.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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