Epigenetics: Histone Modifications and Chromatin Remodelling (2/3)

Published on 1 October 2025 at 12:00

Histone proteins aid in the compaction of DNA in cells and their modification can regulate gene expression. This second essay in a series on Epigenetic Mechanisms delves into how acetylation and methylation of histone proteins, as well as their repositioning along the DNA sequence, can cause this altered gene expression, with a continued discussion of the theme of epigenetic crosstalk which pervades this series.

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Epignetics: Histone Modifications and Chromatin Remodelling

By Ashley Shipley

1 October 2025

1. Introduction:

If all the DNA in a single human cell was to be fully stretched out, it would reach a length of approximately 2 metres. It therefore seems incredible that so much material can fit within the nucleus of the cell, a compartment which is approximately 6 µm in diameter. This miraculous feat is completed through a number of condensation steps, the first involving histone proteins¹. Two copies of four different histone proteins – H2a, H2b, H3, and H4 – come together to form an octamer, around which DNA wraps to produce a nucleosome². Each nucleosome contains these eight histones and approximately 146 bases of DNA, wrapped about 1.67 times around the octamer and subsequent octamers are separated by approximately 80 bases of free or ‘naked’ DNA. This wrapping of the DNA around the histone core is the first stage in the great compaction of DNA which allows its great length to fit within the small nucleus³. Although most of a histone protein can be considered a globular shape around which DNA can coil, they also contain a more relaxed structural element at one end, referred to as the ‘tail’², which doesn’t interact with the DNA directly and can be modified in a number of ways³. These modifications include acetylation, methylation, phosphorylation and ubiquitination among many others^{4, 5}, and can affect the interaction between the histones and the DNA⁶, thereby effecting the compaction of the DNA within the cell. Alternatively, similarly to those discussed in the first essay in this series, Epigenetics: DNA Methylation, these modifications can prevent or encourage the binding of other proteins either to the histone directly or to the associated DNA⁷. Both of these outcomes alter how the associated gene is expressed and are therefore considered epigenetic mechanisms. In this second essay in my series on epigenetic mechanisms, I will discuss in detail the two most common forms of histone modification, acetylation and methylation and I will then go on to discuss a separate but related epigenetic mechanism, chromatin remodelling.

2. Histone Acetylation:

An important epigenetic modification that occurs on histone proteins is the addition of acetyl groups (Ac) otherwise known as acetylation, and this appears to occur exclusively on the various lysine residues on the histone tails². Histones, and indeed all proteins, are composed of a sequence of amino acid residues which determine their structure and function. The loose tails of histone proteins, especially H3 and H4, contain a large number of the positively charged amino acid lysine³ which causes the histone tails, in their natural, unacetylated form, to be generally positively charged, while the DNA that wraps around the histones is negatively charged. The bonding between the DNA and the histone proteins is enhanced by the attraction of these oppositely charged molecules and therefore a tightly closed nucleosome is produced⁸. Due to the close relationship of the DNA and histones within the nucleosome, the DNA can not interact with the transcription machinery which will cause the expression of the associated gene. Therefore, in this unacetylated state, gene expression is reduced⁶. This can be changed, however, by the addition of an acetyl group to lysine residues by a group of epigenetic writers, histone acetyltransferases (HATs). When lysines become acetylated, they lose their positive charge. This reduces the strength of the association between the histone protein and the DNA leading to a more open nucleosome. The transcription machinery is therefore capable of accessing the DNA and can subsequently express the associated gene⁸.

As detailed in the previous essay in this series, writers are not the only group of epigenetic modifiers. Epigenetic erasers, histone deacetylases (HDACs), also exist within the nucleus to remove acetyl groups from lysine residues, restoring the positive charge of the histone and its strong association with the DNA and recreating the closed nucleosome, inaccessible to the gene expression machinery^{6, 9}. As both HATs and HDACs are working within the nucleus at the same time but in conflicting roles, the overall ‘acetylation status’ of any one section of DNA, and therefore the expression status of the associated gene, is a consequence of a complex crosstalk between the two modifiers⁸, perhaps mediated by other factors that determine the localisation of the modifiers to different parts of the genome.

HATs can form part of an activator complex or may exist as an individual entity which can nonetheless bind to other gene activator proteins. Although the unacetylated nucleosome has a closed confirmation inaccessible to the bulky transcription machinery, smaller proteins which also influence gene expression, such as transcription factors, may still be able to bind to some exposed areas, especially those in the ‘naked’ DNA between the nucleosomes⁷. These proteins may recruit HATs to the beginning of genes, the so-called promoter region, which then acetylate available lysines, opening the nucleosome and allowing the transcription machinery access, thereby increasing gene expression. Interestingly, as was described in the previous essay, a positive-feedback loop occurs in which the acetylation is perpetuated across the gene due to the fact that HATs contain a domain that can recognise and bind to the acetyl mark¹⁰. This linkage of writer and reader functions means that once the initial acetylation of the nucleosomes at the promoter occurs, more HATs become localised to that region and begin to acetylate and open-up the nucleosomes further along the gene sequence, allowing its expression.

Similarly to the epigenetic writer, HDACs can form part of a repressor complex or may exist individually, binding to repressors bound to the DNA. The principal job of HDACs is to remove acetylation to close nucleosomes which ultimately leads to reduced gene expression. This end is also achieved by DNA methylation, as shown in the previous essay. As discussed there, DNA methylation marks are read by various proteins including MECP2 which recruits the Sin3 complex of proteins which contains a HDAC⁷. Therefore, this HDAC is recruited to areas of DNA methylation, through binding to a methylation reader, and removes acetyl groups in areas already marked for expression inhibition. This is one way in which epigenetic mechanisms can work together to dynamically effect gene expression.

In conclusion, histone acetylation neutralises the positive charge of lysines of the histone tails which reduces the binding between the histones and DNA, causing the nucleosome to become more open and the associated gene to become capable of being expressed. This process is reversed by histone deacetylation which restores the lysine’s positive charge, the strong relationship between DNA and histone, the closed nucleosome configuration, and the lack of gene expression. Due to interactions with proteins, especially readers of both its own and other epigenetic marks, HATs and HDACs are localised to different areas of the genome and greatly impact the expression of genes.

3. Histone Methylation:

Another epigenetic mechanism concerning histone proteins is methylation. Just like DNA, as discussed in the previous essay, methyl groups can be added to histone tails but, unlike DNA, this process can be quite variable. Firstly, while DNA methylation occurs exclusively on the cytosine residues in a CpG dinucleotide, at least in humans, histone methylation can occur on several lysine, histidine, and arginine residues on the tails of H3 and H4^{3, 10}. Additionally, each individual cytosine in DNA can only accommodate one methyl group, called mono-methylation. For histone proteins, on the other hand, it is common for individual residues to be mono-, di-, and tri-methylated⁷. Finally, DNA methylation is almost invariably associated with gene expression silencing (although DNA methylation can cause activation of gene expression when it occurs within the gene body this may be due to the silencing of transposons) while histone methylation can be associated with either gene expression repression or activation¹¹, as will be discussed further in this section.

As I have compared histone methylation to DNA methylation, it also makes sense to compare it to the previously describe histone modification, histone acetylation. Two of the lysines that are the target of acetylation may also be methylated³ (H3K4 and H3K9 – these will be discussed later) and the mechanism of addition and removal of methylation, specifically to lysine, is similar to that of acetylation, namely histone methyltransferases (HMTs) and histone demethyltransferases (HDMTs), which are used for addition and removal respectively, are akin to the HATs and HDACs discussed previously⁸. However, when arginine residues are monomethylated, the removal of this modification is more akin to the process of DNA demethylation (deamination) as deiminases remove the arginine’s imino group along with the methyl group to produce citrulline⁷. An additional difference between the two histone modifications is the way that they cause changes in gene expression, Acetylation, as discussed above, changes the charge of histone tails and therefore alters the binding between the histone and DNA. Methylation, however, does not influence the charge of the histone protein¹⁰ but, like DNA methylation, either recruits or repels certain proteins necessary for gene expression⁹.

3.1. Histone Methylation Effects:

As previously indicated, the effect of histone methylation may be to increase or decrease gene expression dependent on various factors including the residue methylated, the histone in which it resides and the actual position in the histone tail, and the number of methyl groups added. Regardless of the precise effect, methylation typically results in the attraction of various factors that then go on to enact changes in gene expression. In this section I will discuss just two examples for both increased and decreased gene expression.

Increased: H3K4

The 4^th lysine on histone 3 may be either mono-, di-, or tri-methylated (H3K4me1/2/3) in DNA associated with active genes. H3K4me1 is found in gene enhancers¹⁰, H3K4me3 is found closer to the genes in their promoters⁷, and H3K4me2 can be found in both enhancers and promoters¹². Most H3K4me1 is added by the MLL3 and MLL4 complexes and H3K4me2/3 is added by the SET1DA and SET1DB complexes, all of which include Trithorax-group proteins^{12, 13}. The SET1DA/B complexes include CFP1 which binds to CpG sequences which, as discussed in the previous essay, are enriched in CpG islands within gene promoters so the H3K4me2/3 methyltransferases are localised to these promoters. MLL3/4 complexes include UTX, a H3K27 demethylase, therefore associating the addition of H3K4me1 with the removal of H3K27me. As this latter modification is associated with decreased gene expression, as will be discussed later, the removal of the modification by the same complex that adds the H3K4me1 modification works to enhance gene expression¹².

The H3K4me mark is ‘read’ by a myriad of proteins that contain specific domains, namely PHD fingers, TUDOR domains, and chromodomains⁹. PHD domains are present in subunits of the transcription factor TFIID, the nucleosome remodelling factor (NURF), and histone acetyltransferase complexes. Therefore, H3K4 methylation is associated with increased attraction of expression machinery to, the removal of nucleosomes from, and the addition of acetylation to nucleosomes at gene promoters, thereby increasing gene expression. Tudor domains are also present in acetyltransferase complexes and the transcriptional coactivator SPIN1, aiding this increase in gene expression¹². Finally, CHD1 contains chromodomains and its binding to H3K4me3 is associated with the recruitment of important protein-creating equipment, thereby encouraging the expression of genes^{9, 12}. Importantly, CFP1 and MLL1, components of the methyltransferase complexes, contain PHD domains allowing them to bind to same mark that they help to add. This reader-writer coupling is a common replication and maintenance mechanism for epigenetic marks¹².

H3K4me1 and H3K4me2 are removed by LSD1/2 demethylases and H3K4me3 is removed by the demethylases of the KDM5 family and perhaps KDM2B. KDM5 appears to be unusually active, removing the tri-methylation regularly and rendering the mark unstable¹².

Increased: H3K36

The 36^th lysine on histone 3 may be mono-, di-, or tri-methylated (H3K36me1/2/3) in DNA associated with active genes⁷. The highly abundant H3K36me2 is typically found in promoters or between genes¹⁴ while the comparatively rarer H3K36me3 is commonly found within actively expressed gene bodies⁷. Of the at least eight H3K36 methyltransferases, seven complete the mono- and di-methylation to produce H3K36me1/2, with NSD1-3 being the most important. Only one methyltransferase, SETD2, is capable of adding the final methyl group to produce H3K36me3, however, as SETD2 is not able to add the first two methyl groups, it works with the NSD enzymes to complete the tri-methylation¹⁵.

Like H3K4 methylation, H3K36 methylation is bound by proteins containing domains such as TUDOR, chromo, and PWWP. PHF1 contains a TUDOR domain and binds to the trimethylation mark while also interacting with and regulating the activity of Polycomb repressive complex 2 (PRC2), which will be discussed in further detail later. MRG15 contains a chromodomain which also binds to H3K36me3 and attracts the histone demethylase KDM5B to the nucleosome. As discussed above, members of the KDM5 family remove the H3K4me3 mark so the targeting of this event to the gene-body location of H3K36me3 may be a way to reduce activation of intragenic promoters and the incomplete expression of genes. Finally, there a several proteins that contain PWWP domains the bind to H3K36 methylation but perhaps the most important are NSD2 and DNMT3B. NSD2 is one of the main writers of the H3K36me1/2 mark so its ability to bind to the vary mark that it adds is an important propagation and maintenance mechanism. DNMT3B, on the other hand, is a writer of DNA methylation. Its ability to read the H3K36me3 mark may have an influence in its localisation to the body of genes¹⁴. As discussed in the previous essay, DNA methylation in the gene body can increase gene expression, perhaps through the silencing of intragenic promoters, and so it may be this interaction between H3K36me3 and DMNT3B that provides an important mechanism for the association between the histone methylation mark and increase gene expression.

H3K36me1 and H3K36me2 are removed by the PHD containing KDM2 family while H3K36me2 and H3K36me3 are removed by the KDM4 family. The division of labour between these two families is a way for different methylation states to exist throughout the genome^{14, 15}.

Decreased: H3K9

The 9^th lysine on histone 3 (H3K9) may be di-methylated in the promoters of unexpressed genes, especially areas of low DNA methylation termed CpG islands¹⁶, tri-methylated in both silenced promoters and throughout the associated gene body⁷, and even mono-methylated at the transcription start site of active genes¹⁷. H3K9me1 is added by SETDB1¹⁵, a methyltransferase that is targeted, along with other factors such as the chromatin assembly factor 1 (CAF1) and HP1α, to parts of the genome already marked by other epigenetic mechanisms such as DNA methylation and histone acetylation by its methyl-CpG-binding and TUDOR domains. As H3K9me1 is most commonly targeted to transposons¹⁸, it may have the function of silencing these dangerous elements that have been activated by histone acetylation, thereby increasing the expression of the associated coding genes. This may explain why H3K9me1 is enriched in active genes although it likely has a silencing activity. H3K9me1 is also added by G9a and GLP homo- and hetero-dimers, particularly within the Sin3 complex mentioned in the Histone Acetylation section. The co-targeting of the methyltransferase and the histone deacetylases HDAC1/2 enhances the silencing of the targeted elements and the ability for the methyltransferase to bind to the H3K9me mark maintains and spreads the mark across the element. H3K9me2 can be added by both SETDB1 and the G9a/GLP dimer but also by SUV39H1/2. SUV39H1/2 is recruited to repetitive parts of the genome by the non-coding RNAs that are transcribed from them and catalyses the silencing of the dangerously active element. This is further evidence of different epigenetic mechanisms working together to achieve gene expression regulation^{15, 18}. SUV39H1/2 contains a chromodomain which binds to¹⁹, and is perhaps even activated by¹⁶, the mark. This is an incidence of the coupling of writer and reader functions and allows for H3K9 methylation and therefore reduced gene expression to spread across the gene¹⁹, and more importantly across cell division²⁰. H3K9me3 is also added by G9a/GLP dimers and SUV39H1/2 in a similar way to the di-methylation mark¹⁸.

H3K9me3 binds the protein HP1, which doesn’t just bind SUV39H1/2, further enhancing the coupling of reader and writer²¹, but can also link nucleosomes, essentially compacting and condensing the DNA and causing a reduction in gene expression^{19, 21}. As will be discussed in the final essay in this series, H3K9me2 is associated with X-chromosome inactivation through the binding of other factors¹⁷. Finally, H3K9me2 can be bound by the protein Stella, an inhibitor of TET enzymes. TET enzymes are important for the demethylation of DNA, as discussed in the previous essay, so the di-methylation mark is strongly tied to the inhibition of DNA methylation removal and enhanced gene silencing¹⁶. This is another example of the crosstalk that exists between different epigenetic mechanisms to regulate gene expression.

Finally, H3K9 methylation is removed by various demethylases. The KDM3 and KDM7 families remove H3K9me1 and H3K9me2 while the KDM4 family removed H3K9me2 and H3K9me3. KDM4 also demethylates H3K36me2/3 so these two antagonistic marks may be removed simultaneously. Furthermore, KDM7, also known as PHF8, contains a PHD domain like the KDM2 family that demethylates H3K36me1/2. PHD domains bind to H3K4 methylation so both H3K9 and H3K36 demethylation is targeted to nucleosomes containing H3K4me, thereby creating a mutually exclusive histone code¹⁵.

Decreased: H3K27

The 27^th lysine on histone 3 can be mono-, di-, and tri-methylated (H3K27me1/2/3) throughout inactive genes. H3K27me1 is added by EZH1 while H3K27me2/3 is added by EZH2, both alternative methyltransferase subunits within the PRC2 complex²², which also contains the subunit EED which provides EZH1/2 with its enzymatic ability²⁰. PRC2 is targeted to parts of the genome to be silenced, including the inactive X-chromosome as will be discussed in the final essay in this series, by its various accessory proteins which can bind to DNA and by non-coding RNAs^{2, 15}. Interestingly PRC2 and the H3K9 methyltransferase G9a have been shown to interact with each other, perhaps providing a mechanism for the co-localisation of H3K9 and H3K27 methylation and therefore enhanced condensation and silencing of chromatin²².

As well as acting as a co-activator, the EED subunit within PRC2 can also bind to the H3K27 methylation mark through its WD40 domain, thereby acting as a maintenance mechanism. NSD2, one of the several methyltransferases that catalyse the methylation of H3K36, can bind to H3K27 methylation through its PWWP domain¹⁵. It has been observed that H3K27 and H3K36 methylation do not typically occur on the same nucleosome so either PRC2 or NSD2 may be inactivated through interaction with the other²², thereby ensuring that the activation and repressive marks are segregated through the genome. Finally, CBX7 binds H3K27 methylation through its chromodomain¹⁵. CBX7 is a component of PRC1, a similar polycomb complex to PRC2¹⁹ which instead catalyses the deposition of a separate epigenetic modification, ubiquitination of the 119^th lysine on histone 2A (H2AK119Ub)²¹. This is once again an example of crosstalk between different epigenetic modifications to regulate gene expression.

H3K27 methylation can be removed by a range of demethylases especially of the KDM6 family. The most important member of this family for our purposes is KDM6A, otherwise known as UTX. We previously encountered UTX when discussing the H3K4me1 methyltransferase complex MLL3/4 of which UTX is a part. As indicated in the previous discussion, this associates H3K4 methylation with H3K27 demethylation. Additionally, the KDM7 family, including PHF8, previously shown to demethylate H3K9, also demethylates H3K27¹⁵. Both of these demethylase families provide an explanation for the absence of H3K27me, and indeed other histone methylation marks, on nucleosomes that contain H3K4 methylation.

3. Chromatin Remodelling:

The addition of molecules to the histone proteins is not the only way that histones can be used to regulate gene expression. In fact, a perhaps more effective mechanism for altering the expression of genes is to move the nucleosome to remodel the DNA, or chromatin, structure. The complete removal of nucleosomes is relatively rare and typically occurs during DNA replication and cell division, where some of the nucleosomes present on the parent DNA strand are removed and added to the daughter strand in order to begin the process of replicating histone modifications¹⁶. Additionally, throughout the cell cycle, specific histones may be removed, and variants may be added in their place. For example, H3 may be replaced by variants such as H3.3 and CENPA, the former being commonly patterned with ‘activating’ modifications and associated with increased expression²⁰and the latter being common in inactive regions of the chromosome such as the centromere and is therefore associated with decreased expression²¹. H2A may also be replaced by variants such as H2A.Z and macroH2A. H2A.Z is generally associated with active genes but may also be associated with inactive chromatin when ubiquitinated¹³. MacroH2A is a variant that is associated with X-chromosome inactivation, a process that will be discussed in detail in the final essay in this series²³.

As noted, removal of nucleosomes is not particularly common, especially when compared to the movement of nucleosomes along the DNA. Nucleosome positioning is altered by the enzyme family SWI/SNF²⁴ which may be targeted to histones by one or more of the modifications described previously. Essentially, nucleosomes can be positioned away from gene promoters to allow the expression machinery to bind to the DNA and thereby express the gene. Conversely, nucleosomes can be positioned within gene promoters to block this access and decrease gene expression^{3, 8, 13, 20}. CpG islands, regions of abundant CpG sequence typically in the promoters of genes, tend to contain fewer nucleosomes relative to other areas of the DNA⁶. This indicates that CpG islands, and by extension promoters, contain high levels of ‘naked’ or ‘free’ DNA which is openly accessible for the expression machinery to bind. Therefore, it could be assumed that, especially at so-called ‘housekeeping genes’ where CpG islands are commonly found⁶, gene expression is generally active and requires the activity of the various modifications detailed in this series to become inactivated.

4. Conclusion:

DNA is packaged within the cell through its interactions with histone proteins. These histone proteins may be modified, importantly through acetylation and methylation, exchanged or moved to alter this interaction, attract other factors, and ultimately regulate gene expression. As has been made clear throughout the essay, these epigenetic mechanisms do not work independently of each other. Some amino acid residues that are acetylated by HATs may also be methylated by HMTs. The methylation of certain residues may attract proteins that methylate or demethylate others creating a dynamic histone code that may associate or dissociate two marks within the same nucleosome. The methylation, acetylation, or other modification of histones may act as a target for proteins that move the entire nucleosome along the DNA, compounding their effect. This epigenetic crosstalk is not restricted to histone modifications, however. DNA methylation can be closely tied to histone deacetylation and methylation, both in the form of targeting proteins to areas of gene silencing and simultaneous deposition of epigenetic marks. Non-coding RNAs (ncRNAs) can be important in the targeting of silencing modifications towards the transposons from which they are produced. This theme of epigenetic crosstalk will be expanded in the third essay in this series where the final epigenetic mechanism, ncRNAs, will be discussed as well as an event that requires the combined action of all three explored mechanisms, X-chromosome inactivation.

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