Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Histone H3

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101644

Historical Background

The eukaryotic genome is extraordinarily well organized. This is achieved through the winding of DNA to form continuous arrays of nucleosome, the fundamental repeating unit of chromatin. Each nucleosome consists of ~147 base pairs of DNA wrapped around a core histone octamer (two copies each of histone H2A, H2B, H3, and H4). Based on this, by the association with linker histones (histone H1), the nucleosome arrays are further organized into solenoid conformation and looping domain structures that occur in both interphase and metaphase chromatin. During cell division, global histone protein production is temporally elevated to meet the cellular demands since histone proteins are needed to be deposited into the newly replicated DNA strands before chromatin condensation and chromatids segregation could happen, which subsequently divided the genetic materials into daughter cells.

In the past half century, histone proteins have long been regarded as the bulk materials or inert proteins merely for packaging of the eukaryotic genomic DNA. This concept has not been changed until the last 20 years with the emergence of epigenetics which demonstrated that histone proteins are unprecedented players involved in chromatin remodeling and modulation of gene expressions, leading to diverse biological consequences (Kouzarides 2007). Epigenetics refers to the study of heritable changes in gene expression that does not involve changes to the underlying DNA sequence. In general, three major epigenetic controls exist, including methylation of DNA, posttranslational modification (PTM) of histones, and expression of noncoding RNA (ncRNA) (Holliday 2006). Altogether, these systems shape the theme of modern epigenetics. Here, among the core histones, the current knowledge on histone H3 and its PTMs will be discussed.

Histone H3 Variants

Variants of histone H3 exist based on the degree of homology of their primary amino acid sequences. These variants have different regulatory mechanisms for their expressions, depositions, as well as genome occupancies (the differential enrichment in euchromatic, heterochromatic, centromeric, or telomeric regions). A total of eight histone H3 variants are reported: (a) the canonical variants: H3.1 and H3.2; and (b) the replacement variants: H3.3, the testis-specific H3 variants H3.4 and H3.5, the primate-specific H3 variants H3.X and H3.Y, and the centromere-specific H3 variant CenH3 (Maze et al. 2014). It is believed that the differential and coordinated decoration (i.e., PTMs) on these H3 variants is likely to contribute to their unique functions in a variety of cellular activities.

PTM Marks Identified on Histone H3 and the Resulting Functions

With the advancement of high resolution mass-spectrometry, a growing number of novel PTMs on histone H3 have been revealed. For the reason that H3.1, H3.2, and H3.3 are the more extensively studied histone H3 variants with extremely high degree of amino acid sequence similarity, thereby, the latest PTM information among these three variants will be presented. Up to date, at least 21 kinds of modification on more than 30 amino acid residues of histone H3 have been reported, with lysine residues bearing the most number and diversity of PTMs on them, including acyl lysine marks [acetylation (ac), β-hydroxybutyrylation (bhb), butyrylation (bu), crotonylation (cr), formylation (fo), 2-hydroxyisobutyrylation (hib), malonylation (ma), propionylation (pr), and succinylation (su)], ADP-ribosylation (ar), biotinylation (bio), citrullination (ci), O-GlcNAcylation (glc), glutathionylation (glu), methylation (me), phosphorylation (ph), and ubiquitylation (ub) (Fig. 1). These PTMs are highly decorated at the histone H3 N-terminus and to a lesser extent in the globular/core domain. So far, acetylation, methylation, and phosphorylation of histone H3 are more extensively studied histone H3 PTMs.
Histone H3, Fig. 1

PTMs of human, rat, and mouse histone H3. Up to date, there are at least 21 kinds of modification on more than 30 amino acid residues of histone H3. Data are summarized from recent literature from NCBI and referenced from UniProtKB (Protein knowledgebase of UniProt) and PhosphoSitePlus (PhosphoSite knowledgebase). Globular/core domain is highlighted in gray. Differential amino acids among variants H3.1, H3.2, and H3.3 are also indicated

In general, acetylation and phosphorylation are more dynamic histone marks than methylation. Methylation can take place on both lysine and arginine residues, and these modifications are major determinants for the formation of active and inactive regions of the genome, depending on the sites that are methylated and also the degree of methylation (Zhang and Reinberg 2001). Mono-, di-, or trimethylation of the lysine (Kme1, Kme2, or Kme3) on histone does not affect its positive charge, therefore, the effect of methylation on nucleosome dynamics is expected to be less direct than other PTM marks (such as various acyl lysine marks). These modifications are carried out by a category of enzymes called “lysine methyltransferases” (KMTs). Histone arginine residues can undergo monomethylation (Rme1) and dimethylation (Rme2) by “protein arginine methyltransferases” (PRMTs) (Zhang and Reinberg 2001). Dimethylation can also occur either in a symmetric (me2s) or asymmetric (me2a) manner. Histone methylations are removed by the class of enzymes named “histone demethylases” that remove methyl groups from methylated lysines or arginines (Bannister and Kouzarides 2005). Notably, arginine residues can also undergo deimination, they are irreversibly converted to citrulline after deiminated by a family of enzymes called “peptidyl arginine deiminases” (PADs), a process known as “citrullination” (ci) (Bannister and Kouzarides 2005). Histone acetylations by “histone acetyltransferases” (HATs) neutralize the positive charge of lysine residues, weakening charge-dependent interactions between histones and nucleosomal DNA, linker DNA, or adjacent histones, and thus increasing the accessibility of DNA to the transcriptional machinery. Histone deacetylations by “histone deacetylases” (HDACs) repress transcription through an inverse mechanism involving the assembly of compact and higher order chromatin structure and the exclusion of transcriptional activation complexes (Struhl 1998). The recent finding that acetylation marks can also be decorated on several serine and threonine residues of histone H3 is intriguing in which these marks are linked to cell cycle progression and cellular pluripotency (Britton et al. 2013).

Histone phosphorylation (catalyzed by various histone kinases and reversibly removed by protein phosphatases) has a similar role to acetylation in modulating nucleosome dynamics, which can promote the affinity of chromatin-binding proteins for their targets. Phosphorylations of H3S10 and H3S28 are robust histone PTMs that can bind with 14-3-3 proteins and involved in transcriptional activation of immediate early gene expressions. Interestingly, these PTM marks are also required for chromatin condensation during cell division (Kouzarides 2007). In particular, phosphorylation of H3S31 is special in which this PTM mark occurs only in variant H3.3 and recently it is suggested that H3.3S31 phosphorylation triggers p53 cell cycle arrest to suppress missegregating chromosomes during anaphase (Hinchcliffe et al. 2016).

Besides acetylation, methylation, and phosphorylation, the functions of other less familiar PTMs on H3 are gradually revealed; for the sake of simplicity, the functions of these marks are summarized in Table 1. So, at any particular time or cellular events, the addition/removal of these histone PTM marks by their corresponding writers/erasers is believed to be tightly and faithfully controlled. Moreover, it should be noted that crosstalk of histone PTMs exist such that one PTM can affect the modification of neighboring PTMs. For example, phosphorylation of H3S10 stimulates H3K14 acetylation, whereas methylation of H3K9 antagonizes H3S10 phosphorylation (Kouzarides 2007). As a result, the dysregulation of these histone PTM marks (i.e., miswritten/mis-erased) might lead to aberrant gene expressions and link to the development of human diseases and cancers.
Histone H3, Table 1

Functions of less familiar PTMs on histone H3

PTM on histone H3



ADP-ribosylation (ar)

ADP-ribosylation of histone H3 may stimulate local chromatin relaxation to facilitate the repair process. Histone ADP-ribosylation preceded DNA damage-induced histone H3 phosphorylation, suggesting that ADP-ribosylation of histone participates and plays an important role in DNA repair mechanisms

Monks et al. 2006

β-Hydroxybutyrylation (bhb)

This modification is induced significantly during prolonged fasting in mouse liver and is associated with genes upregulated in starvation responsive metabolic pathways [amino acid metabolism, redox homeostasis, circadian rhythm, and peroxisome proliferator-activated receptor (PPAR) signaling]

Xie et al. 2016

Biotinylation (bio)

Biotinylation of histone H3 plays a role in cell proliferation, gene silencing, and cellular response to DNA damage

Kothapalli et al. 2005

Butyrylation (bu)

Histone H3 butyrylation may provide a novel epigenetic regulatory mark for cell metabolism

Chen et al. 2007

Crotonylation (cr)

Histone lysines are crotonylated or acetylated depends on the relative intracellular concentrations of crotonyl-CoA and acetyl-CoA, thereby linking cellular metabolism to gene expression

Sabari et al. 2015

Formylation (fo)

Histone H3 formylation could potentially impact on chromatin function, and contribute to the pathophysiology of oxidative and nitrosative stress

Jiang et al. 2007

O-GlcNAcylation (glc)

Histone H3 O-GlcNAcylation is another important mechanism that controls cell cycle transition

Fong et al. 2012

Glutathionylation (glu)

Histone H3 is able to sense cellular redox changes through glutathionylation of its cysteine, and this modification produces structural changes affecting nucleosomal stability, leading to a more open chromatin structure, which in turn, might assist replication; and this may explain why glutathionylation of H3 is increased in fast proliferating cancer cells but decreased in aging cells

García-Giménez et al. 2013

2-Hydroxyisobutyrylation (hib)

Histone H3 2-hydroxyisobutyrylation shows distinct genomic distributions from histone Kac or histone Kcr during male germ cell differentiation. The histone Khib mark is conserved and widely distributed and has high stoichiometry and induces a large structural change, suggesting its critical role on the regulation of chromatin functions

Dai et al. 2014

Malonylation (ma)

Histone H3 malonylation is likely to play important roles in histone structure and function

Xie et al. 2012

Propionylation (pr)

Histone H3 propionylation may provide a novel epigenetic regulatory mark for cell metabolism

Chen et al. 2007

Succinylation (su)

Histone H3 succinylation is likely to play important roles in histone structure and function

Xie et al. 2012

Ubiquitylation (ub)

Histone H3 can be ubiquitylated in response to DNA damage and provides other signals important for gene regulation

Wang et al. 2006

Association of Histone H3 with Disease

Histone writers, erasers, and readers with altered activities/recognitions toward histone substrates have been demonstrated to contribute to human diseases and cancers. Recently, mutations on histone H3 have also been identified on H3K27 and H3K36. These oncohistone mutations, which convert the above lysine residues to methionines, lead to glioblastoma (K27M mutation) or chondroblastoma (K36M mutation) (Kallappagoudar et al. 2015). For the reason that in normal humans these two lysines in histone H3 are highly decorated with various types of important repressive and activating PTMs, therefore, the mutation of these lysines to methionines is believed to greatly impact the cellular epigenetic circuits since K27M and K36M mutants can no longer be decorated with the original histone lysine PTMs.


In the past decade, an amazingly growing number of histone H3 PTMs and the corresponding writers, readers, and erasers, as well as the evidence of their interplays to the regulation of cellular processes were uncovered. Given the fact that virtually a variety of biomolecules (e.g., sugars, energy metabolites, and even antioxidants like GSH) can be unexpectedly decorated on histones, it is possible that an unknown number of histone PTMs might exist and yet to be discovered. Nevertheless, it will be an exciting task for scientists for the ongoing discovery of novel histone PTMs and their functions. In this regard, the ultimate goal would certainly be finding the right ways on how to manipulate/edit the epigenome that might cure human diseases and cancers. Suffice to say, the era of epigenetics is on its way.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and GeneticsShantou University Medical CollegeShantouChina