Histone Modifications Guide


Gene expression is regulated by histone modifications, which are post-translational modifications. The most modified histone is histone H3.​​

Post-translational modifications to histones – called marks – regulate gene expression by arranging the genome into active euchromatin regions or inactive heterochromatin regions; in the former region, DNA is accessible for transcription but in the latter region it is more compact and less accessible for transcription.

Histones are capable of packing and ordering DNA into structures called nucleosomes so that it fits within the nucleus of a cell. Two subunits are present in each nucleosome, with each made of histones H2A, H2B, H3 and H4 called core histones. The linker histone H1 serves as a stabilizer.

The most modified histone is histone H3. When this histone is modified, it is possible to differentiate between the functional elements of the genome (gene bodies, enhancers, promoters), predict the type of chromatin (euchromatin versus heterochromatin), and establish whether these elements are in a repressed or active state. The total histone H3 is the most useful control to look for when studying histone H3 modifications.



Figure 1. The most common histone modifications. See our histone modifications poster for more.

Histone methylation

Lysine methylation of histones H3 and H4 is involved in transcriptional repression and transcriptional activation based on the methylation site, whilst transcriptional activation is promoted by arginine methylation1.

Lysines provide functional diversity to each methylation site and they can be either mono-, di-, or tri-methylated. For instance, tri-methylation and mono-methylation of K4 (H3K4me3 and H3K4me1) are active marks, but H3K4me3 and H3K4me1 are found at gene promoters and transcriptional enhancers, respectively. H3K36me3 – tri-methylation of K36 is linked to transcribed areas in gene bodies.

While tri-methylation of K27 and K9 on histone H3 (H3K9me3 and H3K27me3) are both repressive signals, H3K27me3 is only a temporary signal controlling the development regulators. H3K9me3, on the other hand, is a permanent signal that controls heterochromatin formation of chromosomal areas with tandem repeat structures.

Predominantly found at promoters in gene-rich regions, H3K27me3 is closely linked to developmental regulators in embryonic stem cells, such as Sox and Hox genes. Generally, H3K9me3 is present in pericentromeres, telomeres, and satellite repeats, which are all gene poor regions.

H3K9me3 also marks specific families of zinc finger genes (KRAB-ZFPs) as well as retrotransposons. Both marks are detected on the inactive chromosome X, with H3K9me3 mainly found in coding regions of active genes and H3K27me3 found at silenced and intergenic coding regions.

Histone acetylation

Usually, histone acetylation is linked to an open chromatin structure, making chromatin accessible to transcription factors and potentially increasing gene expression considerably 2. Histone acetylation is mainly aimed at promoter regions.

For instance, acetylation of K27 and K9 on histone H3 (H3K27ac and H3K9ac) is generally linked to promoters and enhancers of active genes. Throughout the transcribed genes, low acetylation levels are also found but this function is still not clear.

The enzymes deacetylases (HDACs) and histone acetyltransferases (HAT) are responsible for erasing and writing the acetylation of histone tails. Within histone H3 and H4, lysine residues are favored targets for HAT complexes.

Histone phosphorylation

During transcriptional regulation, cell division, and DNA damage repair3–6, core histone phosphorylation is a major intermediate step in condensation of chromosomes. Histone phosphorylation is different from methylation and acetylation and it appears to function by acting as a platform for effector proteins and establishing communications between other histone modifications. As a result, a downstream cascade of events takes place.

Phosphorylation of histone H2A on T120 and histone H3 phosphorylation at S10 (H3phosphoS10) are mitotic markers – these modifications play a role in the regulation of structure and function of chromatin during mitosis as well as in chromatin compaction. H2AX phosphorylation at S139 (leading to γH2AX) is recognized as one of the earliest events that occur after the breakdown of DNA double-strand.

It acts as a recruiting site for DNA damage repair proteins7,8. Phosphorylation of histones also has a wider role to play – for instance, phosphorylation of H2B allows apoptosis-related DNA fragmentation, chromatin condensation, and cell death9.

Histone ubiquitylation

The two most highly ubiquitylated proteins in the nucleus are histone H2A and H2B10. Monoubiquitylated H2B on K123 (yeast)/K120 (vertebrates) and monoubiquitylated H2A on K119 are the most abundant forms of proteins. Conversely, polyubiquitylated histones have also been defined, for example K63-linked polyubiquitylation of H2AX and H2A.

Polycomb group proteins catalyze H2A monoubiquitylation, which is largely related to gene silencing. Bre1 in yeast as well as its homologs RNF20/RNF40 in mammals is the key enzyme that leads to monoubiquitylated H2B.

Monoubiquitylated H2B, unlike H2A, is linked to transcription activation. Similar to other histone modifications, H2A and H2B monoubiquitylation is reversible and is rigorously controlled by deubiquitylating enzymes and histone ubiquitin ligases.

Ubiquitylation of histones plays a major role during DNA damage response: K63-linked polyubiquitylation of histone H2A/H2AX is catalyzed by RNF8/RNF168 and gives a recognition site for DNA repair proteins, including RAP80. The sites of DNA double strand-breaks also have monoubiquitylation of histones H2A, H2B, and H2AX.

Modifying enzymes

Epigenetic modifications were believed to be irreversible for a long time; stable marks propagated via many cell divisions. Yet, studies have shown that this process is controlled by a specific set of enzymes and is much more dynamic.

The following epigenetic regulators can be categorized into readers, writers, and erasers:

  • Epigenetic writers: Epigenetic marks are added to histones by several enzymes such as kinases, histone methyltransferases (HMTs/KMTs), histone acetyltransferases (HATs), and protein arginine methyltransferases (PRMTs).
  • Epigenetic readers: Epigenetic readers detect and attach to the epigenetic marks laid down by epigenetic writers and thus determines their functional outcome. They include Tudor, proteins containing bromodomains, and chromodomains.
  • Epigenetic erasers: The reversal of epigenetic marks is catalyzed by erasers, like phosphatases, lysine demethylases (KDMs), and histone deacetylases (HDACs).


  1. Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–57 (2012).
  2. Roth, S. Y., Denu, J. M. & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).
  3. Nowak, S. J. & Corces, V. G. Phosphorylation of histone H3: A balancing act between chromosome condensation and transcriptional activation. Trends Genet. 20, 214–220 (2004).
  4. Rossetto, D., Avvakumov, N. & Côté, J. Histone phosphorylation: A chromatin modification involved in diverse nuclear events. Epigenetics 7, 1098–1108 (2012).
  5. Banerjee, T. & Chakravarti, D. A Peek into the Complex Realm of Histone Phosphorylation. Mol. Cell. Biol. 31, 4858–4873 (2011).
  6. Kschonsak, M. & Haering, C. H. Shaping mitotic chromosomes: From classical concepts to molecular mechanisms. BioEssays 755–766 (2015).
  7. Lowndes, N. F. & Toh, G. W.-L. DNA repair: the importance of phosphorylating histone H2AX. Curr. Biol. 15, R99–R102 (2005).
  8. Pinto, D. M. S. & Flaus, A. Structure and function of histone H2AX. Subcell. Biochem. 50, 55–78 (2010).
  9. Füllgrabe, J., Hajji, N. & Joseph, B. Cracking the death code: apoptosis-related histone modifications. Cell Death Differ. 17, 1238–1243 (2010).
  10. Cao, J. & Yan, Q. Histone ubiquitination and deubiquitination in transcription, DNA damage response, and cancer. Front. Oncol. 2, 26 (2012).



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Last updated: Jun 6, 2019 at 12:54 PM


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