Inheritance of epigenetic transcriptional memory

Abstract

Epigenetic memory allows organisms to stably alter their transcriptional program in response to developmental or environmental stimuli. These transcriptional programs are regulated by heritable regulation of the function of enhancers and promoters. Memory involves read-write systems that enable self-propagation and mitotic inheritance of cis-acting epigenetic marks to induce stable changes in transcription. Also, in response to environmental cues, cells can induce epigenetic transcriptional memory to poise inducible genes for faster induction in the future. Here, we discuss modes of epigenetic inheritance and the molecular basis of epigenetic transcriptional memory.

Introduction

An improved understanding of nuclear architecture has begun to reveal how genome organization affects transcription and other biological functions. Chromatin conformation and composition influence gene expression¹. These epigenetically heritable alterations are one of the ways in which cells respond to, and remember, developmental or environmental stimuli. Epigenetic regulation and memory involve mitotically — and sometimes trans-generationally — heritable mechanisms². For example, in worms, fruit flies, mice, and humans, changes in paternal or maternal diet can reprogram the metabolism of offspring in future generations to cause a predisposition towards obesity or associated conditions^3–7. Stable changes in transcription are associated with changes in DNA methylation, post-translational histone modifications⁸, transcription factor activity, non-coding RNA (ncRNA) expression or mRNA stability⁹. Recent experiences can also be remembered for several mitotic cell divisions; some inducible genes exhibit heritable epigenetic transcriptional memory following exposure to a transient stimulus¹⁰. Transcriptional memory poises genes for faster re-activation, allowing cells to better adapt to a previously encountered condition^11–15. Stable transcriptional states and less stable transcriptional memory both involve heritable regulation of promoter and enhancer functions in cis. In this review, we will discuss general molecular mechanisms of heritable epigenetic regulation and, more specifically, epigenetic transcriptional memory.

DNA methylation as an epigenetic regulator of transcription

One of the best-understood mechanisms of heritable transcriptional regulation is the methylation of DNA. The amino group on adenosine is methylated in bacteria, and the C5 position of cytosine is methylated in plants, mammals, and certain fungi like Neurospora crassa¹⁶. However, DNA methylation is not universal; Drosophila has very low levels of cytosine methylation, C. elegans has low levels of adenosine methylation but not cytosine methylation¹⁷, and budding and fission yeasts have no DNA methylation¹⁸.

In mammals, methylation of cytosine in cytosine-guanine dinucleotides (CpG) can be inherited during mitosis because it is re-established following DNA replication. Unmethylated cytosine nucleotides are incorporated into newly synthesized strands during DNA replication, producing hemi-methylated CpGs. These hemi-methylated CpGs are then recognized by maintenance DNA methyltransferase DNMT1, which methylates the cytosines on the daughter strand to re-establish methylation patterns. DNMT1 interacts with replication cofactor PCNA to couple replication to the re-establishment of DNA methylation¹⁹ (Figure 1A). The de novo DNA methyltransferases DMNT3A, DNMT3B, and DNMT3C establish new cytosine methylation on unmethylated sites (Figure 1A). DNMT3A/B/C can be recruited to sites in the genome by transcription factors²⁰, histone modifications²¹, and other mechanisms²⁰.

Figure 1: Epigenetic inheritance mediated by DNA methylation, lncRNAs and histone modifications.

A) DNMT1 is required for recognizing hemi-methylated CpGs and maintaining DNA methylation after replication in organisms with DNA methylation. It interacts with PCNA and is recruited by ubiquitination of histone H3 and PAF15 by UHRF1. LncRNAs can also recruit DNMT1 to chromosomal loci to promote DNA methylation^44,49. DNMT3A/3B establish de novo DNA methylation, particularly during embryogenesis and establishing imprinting. These methyltransferases are important in establishing epigenetic memory via DNA methylation. B) In propagating H3K9me3 in fission yeast, HDAC Clr3 (yellow) is recruited by HP1 and sequence-specific DNA-binding factors (light blue circle) at silencer elements or nucleation sites (NS) to deacetylate histones and reduce histone turnover, thus maintaining the H3K9me3 mark. A certain level of chromatin-bound Clr3 and high H3K9me3 density is required to keep the H3K9me3 mark and promote the dual read-write activity of Clr4^Suv39h (red), which can bind methylated H3K4 via its chromodomain and catalyze methylation of H3K9 to promote the propagation of heterochromatin⁶⁰. C) For H3K27me3 mark in mouse embryonic stem cells, self-propagation involves H3K27me3 marks on parental histones, PRC2 complex, and linker histone H1. The EED reader component of PRC2 complex binds H3K27me3 and the EZH2 writer component of PRC2 catalyzes methylation of H3K27 on adjacent nucleosomes. In mESCs, after H3K27me3 is diluted during DNA replication due to newly incorporated histones (pink), linker histone H1 (yellow) compacts chromatin at heterochromatic regions to promote restoration of H3K27me3 on repressive genes⁶⁵. Repressed chromatin with higher levels of H1 experience rapid re-establishment of H3K27me3 after replication, while active chromatin with lower levels of H1 experience slower rates⁶⁵. D) Establishment of epigenetic memory in yeast and humans requires RNAPII-independent H3K4me2, which promotes SWR1-dependent incorporation of histone variant H2A.Z upstream of poised gene promoters as well as recruitment of poised RNAPII, and interaction with the nuclear pore. This histone mark can be transmitted through mitosis by a proposed mechanism whereby the SET3C reader recognizes H3K4me2, interacts with Leo1, a subunit of Paf1 complex, to recruit a Spp1-deficient version of COMPASS that re-establishes H3K4me2¹⁴.

CpG methylation impacts transcription by promoting stable silencing of many genes, intergenic regions, repeat elements, and transposons during cell differentiation, embryonic development, and X-inactivation^22,23. In mammals, abnormal CpG methylation profiles can result in abnormal gene expression and phenotype⁶. Cytosine methylation can lead to different outcomes based on its context. Methylation near promoters often facilitates transcriptional repression by inhibiting binding of transcriptional activators or methylation-sensitive TFs²⁴ and recruiting repressive methyl-binding proteins. Furthermore, DNA methylation over promoters is anti-correlated with expression of genes associated with differentiation during eye development in mammals,²³. In contrast, DNA methylation in the gene body is associated with gene expression in mammals¹⁹, but has an unclear functional significance in plants²⁵.

Despite the stability and conservation of DNA methylation patterns, aging²⁶, DNA damage²⁷, spaceflight²⁸ or drought stress²⁹ can alter CpG methylation, leading to new, stable methylation profiles and transcriptional patterns. Stress-induced changes in DNA methylation can even prime the future offspring to better tolerate or effectively respond to such stresses³⁰ in a manner reminiscent of epigenetic transcriptional memory. It should be noted, however, that stable transgenerational epigenetic inheritance of DNA methylation, while relatively common in plants, is rare in mammals because of erasure during early embryonic development³¹.

Noncoding RNAs as epigenetic regulators of transcription

Most of the transcriptional output in plants and animals are long non-coding RNAs (lncRNAs)³². LncRNAs are short-lived, >200 bp long, nuclear³³ RNAs that facilitate transcriptional regulation. These transcripts are cell-type specific, transcribed from sequences overlapping or upstream of coding genes. Dysregulated expression of lncRNAs has been implicated in cancer^34–36 and neurodegenerative diseases^37–42. LncRNAs influence transcription by associating with chromatin and influencing the recruitment of enzymes that mark either DNA or histones. Their effects can produce long-term changes in the transcription of the genome (Figure 1A)^43–46. For example, the Xist lncRNA coats the inactive X chromosome, stimulating recruitment of Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2), which methylates histone H3 on lysine 27 and ubiquitinates H2A^44,47, repressing transcription⁴⁸. Likewise, the TINCR lncRNA recruits DNA methyltransferase DNMT1 to chromosomal loci to promote DNA methylation and inhibit transcription (Figure 1A)^44,49. However, lncRNAs can also promote transcription; in response to a stimulus eliciting an immune response, immune gene promoters associate with immune gene-priming lncRNA UMLILO⁵⁰. UMLILO recruits the histone methyltransferase complex WDR5-MLL1, promoting trimethylation of H3K4, which primes them for enhanced response upon subsequent exposure, a form of transcriptional memory⁵⁰. Although there is still much to uncover on the specifics of these mechanisms, it is evident that lncRNAs can function in trans to alter the chromatin landscape to induce heritable changes in transcription.

Histone modifications as epigenetic regulators of transcription

Post-translational modification of histones is associated with shorter-term, less stable epigenetic regulation than CpG methylation. DNA is wrapped around histone octamers, which are comprised of two copies of each core histone proteins H2A, H2B, H3, H4. At the amino terminus of each of these proteins are unstructured, positively charged tails. Chemical modifications of histones within nucleosomes are associated with – and required for – proper transcriptional regulation⁵¹. Transcription is associated with acetylation of histone tails. Histone acetyltransferases are generally recruited to active genes by sequence-specific transcription factors⁵². Histone acetylation neutralizes the net positive charge of histones, reducing their affinity for negatively charged DNA⁵¹, increasing access to DNA, and allowing sequence-specific transcription factors (TFs) to bind. Acetylated lysines on histones also recruit factors and protein complexes with chromatin-modifying or chromatin-remodeling activities⁵¹. Acetyltransferases and deacetylases play critical roles in transcriptional activation and repression and silencing, respectively.

Methylation of histones enables binding by proteins bearing at least ten distinct reader domains, such as chromodomains (for histone H3 lysine 9 methylation), PHD domains (for H3 lysine 4 methylation), and specialized WD40 domains (for H3 lysine 27 methylation). Transcriptional repression is associated with methylation of H3 lysine 9 (H3K9me) over constitutively silenced heterochromatin and H3 lysine 27 (H3K27me) over conditionally silenced facultative heterochromatin⁵³. Meanwhile, active regions are associated with methylation of H3 lysine 4 (H3K4me) and H3 lysine 36 (H3K36me). Thus, histone methylation demarcates different parts of the genome: H3K4me1 at enhancers⁵⁴, H3K4me3 at gene promoters, and H3K36me3 over gene bodies⁵⁴. H3K4me2 marks are found at promoters and gene bodies at both active and poised genes in yeast^55,56. The effects of each of these histone methylation marks reflects their ability to recruit co-repressors such as HP1 (in the case of H3K9me3), histone deacetylases (in the case of H3K27me3) or co-activators histone acetyltransferases (in the case of H3K4me3).

Based on contact frequency between chromosomal regions, chromatin can be organized into at least two distinct compartments called A and B⁵⁷. The A compartment contains active chromatin — nearly all active promoters, distal enhancer elements, and active transcription start sites (TSS) — while the B compartment contains inactive, quiescent chromatin, and most transcription termination sites⁵⁷. The A compartment comprises two subcompartments, A1 and A2, which are enriched for genes and active chromatin marks such as H3K4me1, H3K27ac, H3K36me3, and H3K79me2⁵⁸. While both are gene rich, A2 associates more with H3K9me3, contains longer genes, is replicated later than A1, and is farther from nuclear speckles than A1⁵⁸. The B compartment is made up of subcompartments B1, B2, B3, and B4, of which B1 correlates with features of facultative heterochromatin (i.e., higher levels of repressive mark H3K27me3, lower levels of active mark H3K36me3), B4 with heterochromatin-associated repressive marks (H3K9me3 and H4K20me3), while B2 and B3 do not contain commonly known histone marks^57,58. Thus, histone modifications also reflect genome compartmentalization.

Parental histones and their post-translational modifications (PTMs) can be reincorporated near their original location following DNA replication⁵⁹. Reincorporation, followed by recognition of these marks by “reader” proteins, which recruit “writer” enzymes, can lead to heritable histone modifications. Such read-write inheritance has been demonstrated for H3K9^60,61 and H3K27^62–66 methylation (Figure 1B, 1C) and facilitates inheritance of long-term silencing.

Are histone marks associated with active transcription heritable? Unlike repressive chromatin marks, most histone modifications associated with transcription are not heritable, partially due to the continuous displacement of parental nucleosomes by transcription⁵⁹. Furthermore, epigenetic erasers such as histone deacetylases and demethylases can actively remove marks such as H3K27ac and H3K4me3^11,55 during events such as repression of inducible genes. These factors can also affect the stability of histone marks. Likewise, whereas nucleosomes over repressed chromatin domains are reincorporated through many replication cycles, nucleosomes at active genes are poorly retained through DNA replication^59,65. Thus, in general, histone modifications associated with active transcription are reflective of current transcription and are lost quickly, making them poor sources of heritable epigenetic regulation.

Epigenetic transcriptional memory

An exception to the previous statement comes from work on the phenomenon of epigenetic transcriptional memory, which has been observed in yeast^55,67, flies⁶⁸, plants^69,70 and mammals^6,11. Certain inducible genes remain poised for rapid reactivation for several generations after removal of the inducing stimulus^{11,62,67,68,71,72}, and mitotic inheritance of this type of transcriptional memory requires histone modifications. Memory consists of: 1) activation of inducible genes, 2) upon removal of the stimulus, a poised state (i.e., transcriptional memory) is established at certain genes, 3) memory is inherited through mitosis, and 4) upon a second exposure to the inducing stimulus, these genes are activated more rapidly or more strongly than in naïve cells. This process is akin to priming or acclimation in plants in response to various stresses like drought, heat, salt, irradiation, and pathogens^73–76. In several cases, memory requires a physical interaction with the nuclear pore complex (NPC), which has been shown to play a part in regulating gene expression^11,77,78.

A well-characterized model for memory is a set of yeast genes induced by starvation for the essential sugar inositol. When yeast cells are starved for inositol, target genes like INO1 and CHO1 are activated and rapidly targeted to the nuclear periphery through a physical interaction with the NPC⁶⁷. The interaction with the NPC requires binding of the transcription factors Cbf1 and Put3 do cis-acting DNA zip codes upstream of the promoter^79,80. Re-supplementation of inositol leads to rapid repression of these genes, but they remain poised at the nuclear periphery for ~ four generations^62,71. Retention at the nuclear periphery after repression involves a distinct molecular mechanism from that utilized during active transcription (i.e., different nuclear pore proteins, different transcription factors, different molecular requirements, see Figure 2A). During memory, the nucleosomes over the promoters and 5’ ends of these genes are both unacetylated and possess dimethylated histone H3 lysine 4 (H3K4me2). This combination of low acetylation and H3K4me2 appears to be unique to memory⁵⁵. In the case of the INO1 promoter, memory also leads to incorporation of H2A.Z into upstream nucleosomes (Figure 2A). Finally, the promoters of such poised genes are associated with a pre-initiation form of RNAPII^11,14,55,71. Upon a second exposure to inositol starvation, these genes exhibit faster re-activation, leading to a fitness advantage over naïve cells¹⁴.

Figure 2: Epigenetic transcriptional memory in yeast and mammalian cells.

A) Yeast INO1 memory. Upon primary exposure to a stimulus, the Ino2/4 activators recruit HAT complexes to acetylate histones and thus increase DNA accessibility to transcription factors and the transcriptional machinery. This leads to binding of Put3 and Cfb1 to DNA zip codes (ZIP) and interaction with the nuclear pore complex (NPC). Upon repression, transcriptional memory is established. The Sfl1/Hms2 TF binds to the MRS DNA zip code, leading to interaction with the NPC. This interaction stimulates RNAPII-independent H3K4 dimethylation, H2A.Z incorporation, and binding of poised RNAPII^14,55,71. If the cells are starved for inositol again, INO1 is more rapidly induced. Eventually, memory is lost and the gene relocalizes to the nucleoplasm and the chromatin returns to a repressed state. B) Transcriptional memory in mammals. Following removal of an inducing stimulus, the activated gene is repressed, epigenetic transcriptional memory is established through binding of specific transcription factors (TFs). Memory is associated with maintenance of accessible chromatin and/or through read-write systems to promote H3K4 methylation. Memory can require interaction with nuclear pore proteins, recruitment of a form of Mediator with Cdk8, and poised RNAPII. Once memory is lost, chromatin returns to a repressed hypoacetylated state⁶².

Similar phenomena have been observed in flies responding to hormonal signals⁷⁷, in mammalian cells responding to cytokine signaling and wounds⁸¹, in worms responding to starvation during larval development⁸², and in plants responding to environmental stressors including drought and temperature changes^70,74,76. In some cases, the molecular players are similar. For example, in flies and human cells, the nuclear pore protein Nup98 has been implicated in memory, and a homologous protein (Nup100) is essential for memory in yeast. In these organisms, Nup98 does not localize exclusively at the NPC, so this may not reflect interaction with the NPC^84–84. In flies, Nup98 is not only involved in gene activation^83,84, but it is also required for enhancer-promoter looping and transcriptional epigenetic memory at genes induced by the hormone ecdysone⁶⁸. Likewise, H3K4 methylation is associated with both interferon gamma memory in human cells^11,85 and heat shock memory in plants^86,87. Thus, evolutionarily distant organisms utilize mechanistically similar, mitotically heritable mechanisms to integrate previous environmental stimuli into future responses.

Molecular mechanisms of epigenetic transcriptional memory

H3K4 methylation observed during memory is associated with H3K4me2, but not H3K4me3. This is due to the recruitment of an alternative form of the H4K4 methyltransferase Set1/COMPASS lacking the Spp1 subunit during memory (Figure 1D)⁵⁵. H3K4me2 has a critical role in epigenetic transcriptional memory. This mark is associated with memory in yeast, humans, and plants. Inactivation of Nup100 in yeast, which causes loss of interaction with the NPC and consequently H3K4 methylation, or Nup98 in human cells leads to loss of both H3K4me2 and poised RNAPII^11,14,55,71. Likewise, mutation of H3K4 to alanine or arginine, inactivation of either the writer of H3K4 methylation (Set1/COMPASS) or the putative reader of H3K4me2 (the SET3C complex), leads to loss of both H3K4 methylation and RNAPII⁵⁵. Furthermore, conditional genetic experiments demonstrate that H3K4me2 is essential for recruitment of RNAPII during memory, supporting a critical role for H3K4me2 in promoting RNAPII recruitment¹⁴. A similar relationship between H3K4 methylation and paused RNAPII was also seen in mouse embryonic stem cells, where depletion of a core COMPASS subunit resulted in depletion of H3K4 methylation and a loss of paused RNAPII^11,55,71, which negatively impacted gene expression⁸⁸. However, this is not always true; inactivation of the sole H3K4 methyl transferase (Set1/COMPASS) in yeast does not strongly affect RNAPII activity and has no effect on RNAPII association with active INO1⁵⁵.

The relationship between H3K4 methylation and the NPC is complex. Loss of Sfl1, the transcription factor that mediates interaction with the NPC, or the NPC protein Nup100 (Figure 2A) leads to loss of H3K4me2 during memory _11,14,55. However, loss of H3K4 methylation results in loss of both H2A.Z and Sfl1, the transcription factor that mediates interaction with the NPC¹⁴. This suggests that H3K4 methylation and the interaction with the NPC represent a positive feedback loop—interaction with the NPC promotes H3K4 methylation and incorporation of H2A.Z, which promotes binding of the transcription factor that mediates interaction with the NPC.

Could H3K4me2 be the source of inherited information during memory? In certain cases, H3K4 methylation can be inherited. H3K4 methylation can persist through mitosis in yeast⁸⁹ and is required to perpetuate transcription through multiple cell divisions from a transplanted nucleus in frogs⁹⁰ and the transgenerational effects from a high-fat diet in worms³. However, when an active gene that lacks memory is repressed, H3K4 methylation is quickly lost⁵⁵. This suggests that the stability and heritability of H3K4 methylation is context dependent.

H3K4me2 associated with epigenetic transcriptional memory is the product of a pathway that is mechanistically distinct from H3K4 methylation associated with active transcription. The H3K4 methylation associated with transcription is dependent on RNAPII; Set1/COMPASS is recruited to active RNAPII via the Paf1 complex¹⁴, which binds to the phosphorylated carboxy terminal domain of RNAPII. This type of H3K4 methylation does not require nuclear pore proteins or reader complex SET3C. However, H3K4me2 associated with INO1 memory requires not only Set1/COMPASS and the Paf1 complex, but also Nup100 and SET3C. In fact, one subunit of the Paf1 complex (Leo1) is required for H3K4me2 during memory but does not impact H3K4 methylation at active genes¹⁴. Finally, H3K4 dimethylation during memory does not require RNAPII, which suggests that memory utilizes an RNAPII-independent, Nup100-dependent mechanism to recruit Spp1⁻ Set1/COMPASS. And unlike the H3K4 methylation associated with active transcription, H3K4me2 associated with memory is mitotically heritable.

Can the H3K4me2 mark itself be inherited? INO1 memory requires a specific cis-acting DNA element DNA zip code called the Memory Recruitment Sequence (MRS) that recruits the TFs Sfl1 and Hms2 to mediate interaction with the NPC via Nup100^62,71. Conditional inactivation of Sfl1 disrupts most aspects of transcriptional memory (i.e. localization to the nuclear periphery and RNAPII recruitment). However, once memory has been established, inactivation of Sfl1 has no effect on H3K4me2, which persists and is reintroduced for up to 4 generations¹⁴. Thus, once established, H3K4me2 does not require the NPC to be inherited. This mechanism of inheritance does require the putative reader protein SET3C⁵⁵, suggesting that the recognition of H3K4me2 may function as part of a read-write mechanism of chromatin replication where Spp1⁻ Set1/COMPASS is recruited by SET3C following DNA replication to maintain H3K4 dimethylation.

Mammalian cells exhibit transcriptional memory in response to cytokine signaling. Upon viral, bacterial, or parasitic infection, the interferon gamma (IFN-γ) cytokine is produced. When cells (i.e., macrophages and fibroblasts) previously exposed to IFN-γ are restimulated, they exhibit transcriptional memory, resulting in faster and stronger expression of certain target genes¹². Furthermore, this transcriptional memory can be inherited over multiple generations^11,13, confers more antiviral protection to the cells, and results in increased histone H3.3 and H3K36me3 marks on primed genes, which were associated with faster recruitment of RNAPII, transcription factors, and chromatin factors (Figure 2B)^12,13. Some primed genes in yeast and human cells interact with both nucleoporins and poised RNAPII and exhibit H3K4me2^11,62,85; however poised RNAPII was not seen in mouse fibroblasts nor at all genes that exhibit memory in HeLa cells (Figure 2B)^12,13.

Genes with strong IFN-γ-induced transcriptional memory are often located within clusters and their memory is constrained by Cohesin, which mediates DNA looping, sister chromatid cohesion, and homologous recombination¹³. These genes were also found to have enhanced chromatin accessibility at target gene promoters in primed cells that correlated with faster targeting of transcription factors STAT1 and IRF1 at several guanylate binding protein gene promoters in primed HeLa cells⁹¹. In fact, STAT1 is required for establishment but not maintenance of IFN-γ-induced transcriptional memory in human cells⁹¹.

Another example of transcriptional epigenetic memory in mammals is the inflammatory response. During the first experience of wound repair or inflammation stimulated by an acute stimulus called imiquimod, epidermal stem cells (EpdSCs) develop an epigenetic memory to promote future wound healing via faster gene reactivation upon subsequent exposures. In forming memory in these cells, lncRNAs are transcribed to interact with Mediator and recruit histone remodelers similar to inflammatory TFs, which are required to make chromatin regions near inflammation-induced genes accessible for transcription¹⁵. The accessibility and inflammation-associated histone modifications (mainly H3K4me1, but in some instances H3K27ac) remain at these regions or ‘memory domains’ long after the inflammation and increased transcription levels have subsided¹⁰. In the case of EpdSCs, a cell-type and stimulus-specific TF, STAT3, and stress-response Activator Protein 1 (a protein complex comprised of FOS and JUN proteins) are required for inflammation-induced memory. STAT3 is required for allowing FOS-JUN to access, bind, and establish memory domains. While STAT3 and FOS are reduced after inflammation subsides, JUN—alongside ATF3 and p63—remains bound to memory domains to keep chromatin accessible and primed¹⁰. Upon subsequent exposures, FOS can be quickly recruited to JUN-bound memory domains for rapid reactivation and enhanced expression of inflammation-associated genes in a STAT3-independent fashion¹⁰. Thus, similar to other forms of transcriptional memory, inflammation memory involves an interplay between transcription factors and histone modifications to regulate transcription in cis.

Concluding remarks

Cells utilize epigenetic transcriptional regulation to both stabilize transcriptional states and to remember recent experiences. During development, differentiation is achieved by establishment and maintenance of very stable transcriptional programs through a combination of mechanisms involving DNA methylation, lncRNA-mediated regulation, and histone modifications. These epigenetic mechanisms also mediate transcriptional changes over intermediate timescales. Here we have focused on epigenetic transcriptional memory, which has been observed in diverse eukaryotic organisms in response to diverse stimuli. Various models of transcriptional memory are beginning to reveal new insights into how transcription factors, histone modifications, and chromosome folding can impact future transcription and how this state can be inherited. Depending on the organism and stimuli, distinct mechanisms are used to mediate memory. Thus, while it is unlikely that all forms of epigenetic transcriptional memory utilize the same mechanism; nonetheless, this diversity strongly supports the idea that remembering previous experiences provides a strong fitness advantage.

Figure 3. Inflammation memory.

Upon wound repair or inflammation caused by an acute stimulus (lightning bolt), epidermal stem cells mount a transcriptional response mediated by stress response-associated TFs FOS (light blue) and JUN (navy) and stimulus-specific TFs like STAT3 (red). These three factors are essential in establishing memory following inflammation but STAT3 functions upstream of FOS-JUN. During inflammation, chromatin changes including H3K4me1 (orange circles) and H3K27ac (light yellow circles) are associated with regions that will exhibit memory. Once the inflammation has resolved, memory domains retain some of the H3K27ac but more of the H3K4me1; furthermore, these regions retain JUN as well as other homeostatic TFs (yellow), which are sufficient for their maintenance. Upon subsequent exposure to similar stimuli, FOS is quickly re-recruited to the memory domains in a STAT3-independent manner.