Histone Modifications by different histone modifiers

J. Biol. Sci. Med. (2016) 2 (1): 45-54

Journal of Biological Sciences and Medicine Available online at www.jbscim.com ISSN: 2455-5266

Review Article

Open Access

Histone Modifications by different histone modifiers: insights into histone writers and erasers during chromatin modification Rakesh Srivastava1*, Uma Maheshwar Singh2 and Neeraj Kumar Dubey3 1

Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, Republic of Korea 2 International Rice Research Institute (IRRI), South Asia Hub, ICRISAT, Patancheru, Telangana, India 3 Department of Biotechnology, Central University of Rajasthan, Ajmer, Rajasthan, India

*Corresponding author: [email protected] ARTICLE INFO Article History: Received 8 March 2016 Accepted 24 March 2016 Available online 31 March 2016 Key words: Epigenetics; Chromatin; Histone modification; Posttranslational modifications; Transcription

ABSTRACT A major mechanism regulating eukaryotic cell gene expression is dynamic DNA packaging into strings of nucleosomes. Nucleosomes and their histone components are usually identified as a negative regulatory to gene transcription. The complex regulation of chromatin structure and nucleosome assembly directs accessibility of the RNA polymerase II transcription machinery to DNA that consequently leads to gene transcription. Post-translational modifications of histone proteins are central to the regulation of chromatin structure, playing essential functions in modulating the activation and repression of gene transcription. This review highlights the different types of histone modifications and their different types of modifiers that influence chromatin structure during transcription.

Copyright: © 2016 Srivastava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

epigenetics was formulated as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" (Berger et al. 2009).

Introduction The term “Epigenetics”, which was first coined by C. H. Waddington in 1942, was adapted from the Greek word “epigenesis” which initially defined the influence of genetic processes on development (Waddington 2012). The term “epigenetics” is described as the study of heritable changes in gene expression by modifying chromatin structure that takes place independently or in the absence of alteration in the original DNA sequence. In the other words, a change in phenotype without a change in genotype. During Cold Spring Harbor meeting in 2008, a consensus definition of the

Two major types of epigenetic modifications, histone modification and DNA methylation have significant effects on gene expression and regulation. The post-translational modifications of histone are referred as “Histone Code” (Strahl and Allis 2000). DNA methylation involves the addition of a methyl group to cytosine residue in the CpG dinucleotide, mediated by enzymes called as DNA methyltransferases 45

Srivastava et al /J. Biol. Sci. Med. (2016) 2 (1): 45-54

(DNMTs). DNA methylation patterns are established and maintained by three main enzymes, such as DNMT3A and DNMT3B are de novo methyltransferases and DNMT1 is mostly accountable for sustaining DNMT and confirms that CpG methylation forms are copied significantly in the course of each cell division (Klose and Bird 2006).

expression. Extracellular or intracellular inputs critically link between metabolism and histone modifications. Many of the enzymes that add or remove histone modifications are known to be sensitive to changes in extracellular or intracellular metabolism signals (Fig.1). In particular, the enzymes that add chemical group to the tail or globular regions of histone and create the various modification states of histone are known as the ‘writers’ of histone modifications, for example, GCN5 is the catalytic subunit of SAGA complex and acetylates histone lysine residue (Baker and Grant 2007; Srivastava et al. 2014; Srivastava et al. 2015). Histones with these post-translational modifications recognized by other groups of proteins are called the readers, such as bromo domains, present in GCN5 and SPT7 subunit of SAGA complex, recognize acetylated lysines residue of histone (Baker and Grant 2007; Yun et al. 2011; Srivastava et al. 2015). Modified histones dynamically reversed to their original states by enzyme is known as erasers, for instance, yeast SIR2 and its human homolog SIRT1 deacetylates histone H4 at lysine 16 (H4K16ac) (Liu et al. 2009). Indeed, a dynamic interaction between histone writers, readers and erasers establish distinct histone marks during different states of transcription cycle. Two different mechanisms have been suggested to elucidate how histone posttranslational modifications affect their influence on gene expression (Kouzarides 2007; Izzo and Schneider 2010). The first mechanism is focused on the alteration of interaction between histones and DNA or between different histones in adjoining nucleosomes consequently, these changes affect higher-order chromatin structural organization to stimulate the gene activation. The second mechanism predicts the recruitment of various regulatory proteins that bind to histone tails (act as a binding platform for these proteins) and these interactions results in the beginning of appropriate biological and cellular functions during transcription (Kouzarides 2007).

The several kinds of chemical modifications occur on the histones at different amino acid residues, which mainly include acetylation, phosphorylation, methylation and ubiquitylation, as well as other modifications such as ADP ribosylation, β-N-acetylglucosaminylation, butyrylation, citrullination, crotonylation, formylation, hydroxyisobutyrylation, hydroxylation, malonylation, proline isomerization, propionylation, sumoylation and succinlylation (Huang et al. 2014). Identification of 130 various histone post-translational modifications sites on the histones of humans further reveals a different paradigm of their roles and advancing the more complication of chromatin-based related pathways (Tan et al. 2011). These histone modifications commonly occur within the histone amino-terminal or carboxy-terminal tails extended from the surface of the nucleosome but they also exist in their globular core regions of histone proteins (Bannister and Kouzarides 2011). Interestingly, dynamic and reversible histone modifications are not only essential for gene regulation and chromosome structure, but also important for cotranscriptional interactions to RNA polymerase II carboxy terminal domain (RNAPII CTD) (Srivastava and Ahn 2015).

Writers, readers and erasers of Histone modifications Post-translational modifications of histone play a major role in the regulation of the gene

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Fig. 1. Extracellular or intracellular inputs influence the histone modifiers to modify the chromatin structure. There are two types of chromatin, heterochromatin and euchromatin. Heterochromatin is highly condensed and transcriptionally inactive chromatin region, whereas euchromatin is transcriptionally active lightly packed chromatin region. Cellular metabolites such as acetyl coenzyme A (acetyl-CoA), adenosine triphosphate (ATP), flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD+), or S-adenosylmethionine (SAM) regulate gene expression by contributing as cofactors for histone modifiers.

HATs: HAT-A and HAT-B. The type-A HATs are a more diverse family of enzymes than the type-B HATs (Bannister and Kouzarides 2011; Steunou et al. 2014). The type HAT-A proteins are present in the nucleus and type HAT-B is predominantly cytoplasmic. HATs can be classified into distinct groups: the GNATs (Gcn5-related Nacetyltransferases), the MYST HATs (MOZ, Ybf2/Sas3, Sas2, and Tip60), the CBP/p300 (CREB-binding protein), SRC family (Steroid Receptor Coactivator, also known as p160 family) and others (such as yeast TAF1 and NUT1) (Steunou et al. 2014).

Histone Acetylation Histone acetylation is first reported in 1964 (Allfrey et al. 1964) and highly dynamically regulated by two groups of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Fig. 2) (Zentner and Henikoff 2013). HAT enzymes catalyze the transfer of an acetyl group from acetyl coenzyme A (acetyl-CoA) to ε-amino group of a histone lysine residue. This transfer neutralizes the positive charge of the histone lysine residue and weakens the interactions with negatively charged nucleosomal DNA and adjacent nucleosomes, resulting in an open chromatin structure that increases the DNA accessibility to the transcriptional proteins or machineries (Zentner and Henikoff 2013). There are two main types of

HDAC enzymes dynamically reverse the effects of HATs and remove lysine acetylation, which results in reestablishing the lysine positive charge and stabilization of the chromatin structure 47


(Bannister and Kouzarides 2011). On the basis of sequence homology and phylogenetic analysis, HDACs are classified into four groups: Groups I and II comprising enzymes that are homologous to yeast Rpd3 and Hda1, respectively. Group III, also

referred to as sirtuins, is homologous to yeast Sir2, and Group IV has only a single member, human HDAC11 or Drosophila HDACX (Steunou et al. 2014).

Fig. 2. Writers and erasers of histone modifications. Among several histone modifications, four main modifications highly associated with chromatin dynamics are: histone acetylation, histone methylation, histone phosphorylation, and histone ubiquitylation. Enzymes in blue color represent the writers for histone modifications, whereas enzymes in red color represent the erasers for histone modifications.

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arginine N-methyltransferases (PRMTs) (Bannister and Kouzarides 2011; Greer and Shi 2012). PRMTs transfer a methyl group to the ωguanidino group of arginine from SAM. The enzyme type-I produces arginine monomethylation (Rme1) and asymmetrically arginine dimethylation (Rme2as), while the enzyme type-II creates Rme1 and symmetrically arginine dimethylation (Rme2s) (Izzo and Schneider 2010).

Histone Methylation Histone methylation is also a reversible process and mainly takes place on the nitrogen side chain of lysines and arginines. Histone methylation is dynamically regulated by histone methyltransferases (HMTs) and histone demethylases (HDMs) (Fig. 2). Histone methylation does not modify the charge of the histone protein, but addition of methyl groups to histone residues creates steric bulk and eliminates a potential hydrogen bond donor, thus disturbing the interactions between DNA and histones to disrupt the chromatin structure (Bannister and Kouzarides 2011; Srivastava and Ahn 2015). Histone methylation on lysine and arginine residues displays different modification patterns: lysines can be mono methylated, di methylated, or trimethylated on ε-amine group, whereas, arginines can be monomethylated, symmetrically dimethylated or asymmetrically dimethylated on their guanidinyl group (Greer and Shi 2012).

Histone demethylases (HDMs) remove methyl groups from histone. The first histone lysine demethylase was recognized in 2004, suggesting that histone methylation is also a dynamic reversible process (Shi et al. 2004). The histone demethylases families are of two types based on the homology and catalytic mechanisms, which use a distinct reaction process to facilitate histone demethylation, where first family member of an amine oxidase domain comprising HDMs is lysine demethylase 1 (KDM1) and second member groups contain catalytic jumonji C (JMJC)domain. These enzymes are highly evolutionarily conserved from yeast to humans and plants. The KDM1A/B (also called as LSD1/2) family is catalyzed amine oxidation reaction by oxidative cleavage and the use of flavin adenine dinucleotide (FAD) as co-factor (Izzo and Schneider 2010; Zhang et al. 2012). The demethylation reaction by LSD family involves protonated nitrogen and consequently mediates demethylate only on monomethylated lysines and dimethylated lysines, but not trimethylated lysines residue. The JMJC family of HDMs utilize a dioxygenase reaction and Fe(II) and 2-oxoglutarate as co-factors for demethylating mono‑, di- and trimethylated lysine residues, which is a radical attack based mechanism. Saccharomyces cerevisiae comprises five JMJC domain-containing histone demethylases: Gis1, Jhd1, Jhd2, Ecm5, and Rph1. In human, there are almost 21 JmjC domaincontaining KDMs present grouped into seven subfamilies KDM2, KDM3, KDM4, KDM5, KDM6, KDM7 and KDM8 Izzo and (Schneider 2010; Black et al. 2012; Zhang et al. 2012).

Several histone lysine methyltransferases (KMTs) have been identified and SUV39H1 was first to be recognized that targets histone H3 at lysine 9 (H3K9). There are three lysine KMTs in Saccharomyces cerevisiae (KMT2/Set1, KMT3/Set2 and KMT4/Dot1) and eight (KMT1 to 8) in mammals (Allis et al. 2007; Black et al. 2012). Interestingly, all of the KMTs that methylate Nterminal lysines comprise SET domain which possesses the enzymatic activity except the Dot1 enzyme, which does not encompass SET domain. Histone KMTs catalyze S-adenosylmethionine (SAM) and the transfer of a methyl to a lysine's εamino group (Black et al. 2012). Histone lysine methylations are associated with activation for example histone H3 methylation at lysine 4 (H3K4me), histone H3 methylation at lysine 36 (H3K36me) and repression for example histone H3 methylation at lysine 9 (H3K9me) of transcription (Kouzarides 2007; Black et al. 2012; Srivastava and Ahn 2015). Two types of arginine methyltransferase are identified, the type-I and type-II enzymes, and together they form large protein family comprising of 11 proteins, which are known as protein 49


removal of phosphate groups from phosphorylated histones, for example, histone H3 at serine (H3S10P) and H3S28P are dephosphorylated by protein phosphatase 1 (PP1; Glc7 in yeast) (Crosio et al. 2002; Rossetto et al. 2012). The PP1 isoform protein phosphatase 1 γ (PP1γ) dephosphorylates the phosphorylated histone H3 at threonine 11 (H3T11P) (Qian et al. 2011).

Histone Phosphorylation Phosphorylation of proteins is one of the most common posttranslational modifications and histones comprise specific phosphorylation sites present on both the core histones and linker histone H1. Similarly to histone acetylation and methylation, histones phosphorylation is a highly dynamic process (Fig. 2). The phosphorylation of histones predominantly occurs on serines, threonines and tyrosines, whereas phosphorylation at histidine of the histone H4 is also reported. In particular, the histone phosphorylation sites are present within the N- or C-terminal tail. The phosphorylation sites within the core regions of histones proteins are also found (Banerjee and Chakravarti 2011). The phosphorylation of histones adds a significant negative charge to the histones, which affects electrostatic interactions in chromatin and facilitates the similar role to acetylation of histone in modulating chromatin dynamics (Banerjee and Chakravarti 2011). The histones are phosphorylated by protein kinase that act as a writer (Rossetto et al. 2012; Mehta and Jeffrey 2015). There are several broad ranges of protein kinases that phosphorylate histone but, their classification is not yet well established like histone acetylation and histone methylation, and also with respect to histone phosphorylation modification. Protein kinases contain a characteristic kinase domain, which catalyze the transfer of gamma-phosphate group from ATP to the hydroxyl group of the target side chain of amino acid. Histone phosphorylation occurs during several cellular responses such as DNA damage and repair, transcription and chromatin compaction during cell division and apoptosis for example, the phosphorylation of histone H3 at serine 28 (H3S28P) is modified by Aurora B kinase (yeast homolog Ipl1) during chromosome condensation (Goto et al. 2002). Protein kinase MSK1 phosphorylates histone H2A at serine 1 (H2AS1P) and inhibits transcription (Zhang et al. 2004). Protein kinases such as AMPK, PKCβ, JAK2, or CDK2 also phosphorylate histone during transcription (Rossetto et al. 2012). Protein phosphatases that act as an eraser and catalyze the

Histone Ubiquitylation While above described histone modifications involve relatively small chemical group changes to amino-acid side chains, in contrast, ubiquitylation occur as a result of 76amino acid larger polypeptide known as ubiquitin, which is attached through covalent modification to histone substrate. Three enzymes, E1-activating, E2-conjugating and E3-ligating enzymes mediate conjugation of ubiquitin to the histone protein (Fig. 2) (Weake and Workman 2008; Cao and Yan 2012). First, ubiquitin is attached to an E1 ubiquitin-activating enzyme on the active site cysteine through a thioester bond. After activation, ubiquitin is transferred to cysteine residue of an E2 ubiquitin-conjugating enzyme. Finally, an E3 ubiquitin-protein ligase transfers the ubiquitin to the ε-amino side chain in the target protein. There are specific histone E2 ubiquitin-conjugating enzyme, Rad6 (Radiation sensitivity protein 6), and a specific histone E3 ubiquitin ligase enzyme, Bre1 (Brefeldin A-sensitivity protein 1), present in budding yeast S. cerevisiae (Cao and Yan, 2012; Fuchs and Oren, 2014). In humans, various types of histone E2s and E3s are identified for instance, UBE2E1 (also called UbcH6), UBE2A/B (also called RAD6A/B), BAF250B and UBE2D3 (also called UbcH5c) for E2 enzymes and CUL4A (Cullin 4A), MSL2 (Male-specific lethal 2 homologue), RING1A/B, and RNF20/40 (Ring finger protein 20/40) for E3 enzymes. Although, ubiquitylation of histone modification is occurred by large polypeptide, it is still a highly dynamically regulated process. The histone monoubiquitylation modification can be reversed by deubiquitin enzymes such as Ubp8 or Ubp10 in yeast and by the ubiquitin-specific peptidases 50


USP3, USP22, USP42 or UBP12/46 in humans (Cao and Yan, 2012).

ARTD1 (also known as PARP1) and ARTD2 (also known as PARP2) mainly present in the nucleus, whereas the other ARTDs are found in the cytoplasm and nucleus, or only in the cytoplasm (Hottiger 2015). Recent reports suggested that ARTD1 modifies all four core histones in vitro, ARTD3 (also known as PARP3) modifies with histones H2B and H3, ARTD10 (also known as PARP10) mono-ADP-ribosylates all four core histones and histone H1, while ARTD14 (also known as PARP7) modifies only the core histones (Messner et al. 2010; MacPherson et al. 2013; Hottiger 2015).

Histone ADP ribosylation ADP-ribosylation is also a reversible covalent posttranslational modification that is conserved in all organisms from bacteria to humans, however, it is not reported in yeasts yet (Hottiger 2015). Histone ADP-ribosylation modification influences the DNA replication, DNA repair, cell cycle regulation, replication and transcription regulation. ADP-ribosylation process involves the addition of ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD+) to amino acid of protein substrate, which is catalyzed mainly by ADP-ribosyltransferases (ARTs) and a subgroup of NAD+-dependent sirtuins. Modification by ADP-ribosylation induces high negative charge to the histone (Messner and Hottiger 2011).

Histone Sumoylation Sumoylation functions as a complex regulator of chromatin modification, transcription, and genome stability. Sumoylation involves the covalent binding of small ubiquitin-like modifier (SUMOs, 11 kDa) molecules to the histone. Mechanistically, sumoylation takes place through an enzyme cascade similar to ubiquitylation process. Sumoylation takes place by the action of the E1 activating enzyme such as Aos1 and Uba2 proteins in yeast, E2 conjugating enzyme like yeast Ubc9, and E3 ligases enzymes such as yeast Siz1, Siz2, Mms21, and Zip3 (Cubenas-Potts and Matunis 2013; Texari and Stutz 2015). Sumoylation affects protein-nucleic acid or protein-protein interactions either by steric hindrance or by prompting conformational alterations (Texari and Stutz 2014). Sumoylation is also a highly dynamic process and is reversed by desumoylating enzymes. S. cerevisiae has only a single SUMO, while mammals have four paralogs, SUMO-1, SUMO-2, SUMO-3, and SUMO-4 (Kerscher 2007; Cubenas-Potts and Matunis 2013). In S. cerevisiae, all four core histones are modified by SUMO and are involved directly in transcriptional repression (Nathan et al. 2006). Modification of histone H4 at lysine 12 by SUMO3 reveals that sumoylation could mediate transcriptional repression by interfering chromatin compaction (Dhall et al. 2014).

Accumulating evidences suggested that histones can be mono- and poly-ADP ribosylated (Messner and Hottiger 2011; Hottiger 2015). The mono-ADP-ribosylation (also known as MARylation) of histone is mediated by the monoADP-ribosyltransferases and has been detected on all four core histones, as well as on the linker histone H1. Poly-ADP-ribosylation (also known as PARylation) of histones is mediated by the polyADP-ribose polymerases (PARPs). The paradigm of histones ADP-ribosylation sites is yet to be determined. Two families of enzymes ADPribosyltransferases are classified: clostridial toxinlike ADP-ribosyltransferases (ARTC) facilitate cytoplasmic and extracellular membraneassociated ADP-ribosylation process and diphtheria toxin-like ADP-ribosyltransferases (ARTDs, formerly known as PARPs) facilitate cytoplasmic and nuclear ADP-ribosylation process (Hottiger et al. 2010). The two groups of enzymes, ADP-ribosylhydrolases and PAR glycohydrolases, reverse histone poly-ADP-ribosylation marks. In human, there are three ADP-ribosyl hydrolases and one poly-ADP-ribose glycohydrolase described (Oka et al. 2006; Messner and Hottiger 2011). There are 18 different types ARTDs present, 51


several other newly recognized modifications, along with the crosstalk among these modifications. The histone codes or posttranslational modifications of histones are key mechanisms for several cellular processes, including regulation of the gene expression and chromatin modification. Accumulating evidences indicate that the significant role of histone modifications is to direct the recruitment or activity of downstream effectors. With the recent development in high throughput screening or mass-spectrometrical sensitivity, some uncharacterized modifications on histone have been recognized in vivo, but how these modifications occur and their functional roles are subject to be determined. Major progresses have been made in recent years concerning how histone modifying enzymes are regulating the addition or removal of chemical groups to histones, however, many remain to be uncovered. It is also interesting to identify novel writers or erasers for unravelling the uncharacterized histone modifications.

Histone O-GlcNAcylation The monosaccharide, β-Nacetylglucosamine (GlcNAc), is conjugated to the hydroxyl group of serines and threonines to generate an O-linked β-N-acetylglucosamine (OGlcNAc) residue. This post-translational protein modification is known as O-GlcNAcylation, which is equivalent to protein phosphorylation and a reversible process (Hart et al. 2007). Interestingly, in mammalian cells, there is a single enzyme, β-N-acetylglucosaminyltransferase (also known as O-GlcNAc transferase or OGT), which catalyzes the transfer of the sugar moiety from the donor substrate, UDP-GlcNAc, to the target protein. The β-N-acetylglucosaminidase (also called as O-GlcNAcase or OGA) enzyme is capable of eliminating the sugar moiety (Zachara and Hart 2004; Hart et al. 2007). Like, most of the other histone post translation modification, OGlcNAc modification is also a highly dynamic process with high turnover rates (Hart et al. 2007; Sakabe et al. 2010; Bannister and Kouzarides 2011). Transcription is regulated by glycosylation modification on RNA polymerase II CTD, histones, chromatin-remodeling factors and transcription factors (Nagel and Ball 2015; Srivastava and Ahn 2015). Recent reports indicated that all histones are also modified by sugar residues O-GlcNAc (Sakabe et al. 2010; Zhang et al. 2011). In humans, all four core histones of the nucleosome are subject to glycosylation modification in the relative order H3, H4 or H2B, and H2A (Zhang et al. 2011). Accumulating evidence revealed that histone glycosylation occurs at various sites of core histone such as histone H2A at threonine 101, histone H2B at serine 36 and serine 112, histone H3 serine 10 and threonine 32, and histone H4 at serine 47 (Sakabe et al. 2010; Fujiki et al. 2011; Zhang et al. 2011; Fong et al. 2012).

Conflict of interest: The authors declare no conflict of interest.

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