J Biosci (2020)45:135 Ó Indian Academy of Sciences DOI: 10.1007/s12038-020-00099-2 (0123456789().,-volV)(0123456789().,-volV) Review Evaluation of post-translational modifications in histone proteins: A review on histone modification defects in developmental and neurological disorders 1 1 2 SHAHIN RAMAZI ,ABDOLLAH ALLAHVERDI * and JAVAD ZAHIRI 1Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Jalal Ale Ahmad Highway, P.O. Box: 14115-111, Tehran, Iran 2Bioinformatics and Computational Omics Lab (BioCOOL), Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Jalal Ale Ahmad Highway, P.O. Box: 14115-111, Tehran, Iran *Corresponding author (Email, [email protected]) MS received 2 March 2020; accepted 14 September 2020 Post-translational modification (PTM) in histone proteins is a covalent modification which mainly consists of methylation, phosphorylation, acetylation, ubiquitylation, SUMOylation, glycosylation, and ADP-ribosylation. PTMs have fundamental roles in chromatin structure and function. Histone modifications have also been known as epigenetic markers. The PTMs that have taken place in histone proteins can affect gene expression by altering chromatin structure. Histone modifications act in varied biological processes such as transcriptional activation/inactivation, chromosome packaging, mitosis, meiosis, apoptosis, and DNA damage/repair. Defects in the PTMs pathway have been associated with the occurrence and progression of various human diseases, such as cancer, heart failure, autoimmune diseases, and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Histone modifications are reversible and used as potential targets for cancer therapy and prevention. Recent different histone PTMs have key roles in cancer cells since it has been shown that histone PTMs markers in cancers are acetylation, methylation, phospho- rylation, and ubiquitylation. In this review, we have summarized the six most studied histone modifications and have examined the role of these modifications in the development of cancer. Keywords. Chromatin; disease; histone proteins; histone modifications; post-translational modifications Abbreviations: ADP, adenosine diphosphate; ADP-ribose, adenosine diphosphate ribose; ART, ADP- ribosyltransferases; ARTD1/ PARP1, poly [ADP-ribose] polymerase 1; ATM/ATR, ATM/ATR serine/threonine kinase; ATP, adenosine triphosphate; BRCA1, breast cancer type 1 susceptibility protein; CARM1, coactivator- associated arginine methyltransferase 1; ChIP, combines chromatin immunoprecipitation; ChIP-seq, ChIP- sequencing; CRC, colorectal cancer; DMFS, distant metastasis-free survival; DNase I, deoxyribonuclease I; DSBs, DNA double-strand breaks; E1, ubiquitin/sumo activating; E2, ubiquitin/sumo conjugating; E3, ubiquitin/sumo ligase; EZH2, Zeste homolog 2; HATs, histone acetyltransferases; HDAC, histone deacetylase; HMTs, histone methyltransferases; HP1, heterochromatin protein; LSD1, lysine-specific histone demethyla1; MAP kinase, mitogen-activated protein kinase; MARTs, mono-ADP-ribosyltransferases; MLL gene fusion, MOZ/MORF (MYST family) gene fusion; NAD, nicotinamide adenine dinucleotide; NATs, N-terminal acetyltransferases; OS, overall survival; PAR, polymeric ADP-ribose; PARP, poly-ADP ribose synthetase; PcG proteins, polycomb group (PcG) proteins; PO4, phosphate; PRC2, polycomb repressive complex 2; PRMTs, protein arginine methyltransferases; PTMs, post-translational modifications; RING, really interesting new gene; RNF20, ring finger protein 20; SET domain, Su(var)3-9, enhancer-of-Zeste and Trithorax (suppressor of variegation, Enhancer of Zeste, and Trithorax); SUMO, small ubiquitin related modifier; TSSs, transcription start sites; USP22, ubiquitin-specific peptidase 22. http://www.ias.ac.in/jbiosci 135 Page 2 of 29 S Ramazi, A Allahverdi and J Zahiri 1. Introduction associate together, and then with two H2A/H2B 1.1 Histone proteins dimers make the histone octamer. In physiological salt conditions, the H3/H4 tetramer is the core of histone DNA in eukaryotic organisms is organized in a octamer, and the H2A/H2B is symmetrically placed nucleoprotein complex called chromatin (Jenuwein and on each side of the tetramer. Approximately 75% of Allis 2001). In recent years it has been shown that the core histone protein mass comprises the ‘histone chromatin has a key role in the regulation of gene fold’ domains which form the spool onto which the expression. Understanding chromatin structure and nucleosome DNA is wrapped. The core histones are dynamics is of fundamental importance for life science highly conserved proteins even from yeast to human, and contributes decisively to our knowledge of cell and this property is very important for the mainte- function, organism development, and treatment of nance of genomic material. The remaining *25–30% diseases. In the eukaryotic nucleus, the proteins which of the mass of the core histones consists of the largely bind to DNA to form chromosomes are divided into structurally undefined but highly evolutionarily con- two groups: the histone and the non-histone proteins. served ‘tail’ domains. X-ray crystal structures of the The complex of both groups of protein with the nuclear nucleosome core particle show that the tail domains DNA is known as chromatin. The total histone mass in follow the minor grooves of DNA to the exterior of chromatin is approximately equal to the DNA (Bow- the nucleosome. man and Poirier 2014; Bulger 2005; Crane-Robinson The tails of histone H3 and H2B follow aligned et al. 1997; Olins and Olins 2003; Xhemalce et al. minor grooves between adjacent DNA super-helical 2011; Zhang and Dent 2005). Histone proteins are gyres, while those of H2A and H4 follow minor responsible for the first and most basic level of chro- grooves over or under the top/bottom super-helical mosome organization, consisting of the nucleosome, turns such that the bulk of the tail domains exit to the which was discovered in 1884 by Albrecht Kossel exterior of the nucleosome and cannot be structurally (Chen et al. 2014). located in the NCP crystal (Bulger 2005; Luger et al. Most of the chromatin in the cell is in the form of a 1997). These histone tails do not contribute to estab- 30-nm filament throughout most of the cell cycle, and lishing the structure of individual nucleosomes signif- at interphase, appears to be looped onto the nuclear icantly; however, they play an essential role in matrix. At mitosis, the 30-nm filament is subjected to regulating the condensation degree of chromatin into further levels of folding to give the highly dense higher-order structure (Peterson and Laniel 2004; metaphase chromosome in which the overall length Sawan and Herceg 2010). In vitro, removal of the compaction of the DNA is about 10,000-fold. The histone tails results in nucleosomal arrays that cannot 30-nm filament is not a suitable template for tran- scription by the large eukaryotic RNA polymerases and clearly has to be unfolded first; formation of an ‘open’ (‘transcriptional competent’) chromatin state is an essential prerequisite for transcription (Sawan and Herceg 2010). The nucleosome is the fundamental repeating unit of chromatin and is the first level of compaction of DNA in eukaryotes (Maleszewska et al. 2016;Mu¨ller and Muir 2014; Shogren-Knaak et al. 2006). Each nucleosome consists of a 145–147 bps DNA molecule wrapped around a histone octamer which comprises two copies of four histone proteins, H2A, H2B, H3 and H4 (Cao and Yan 2012; Mal- eszewska et al. 2016; Rogakou et al. 1998; Stu¨tzer et al. 2016) (figure 1). The nucleosomes are joined by linker DNA and histone H1 to form chromatin (Crane-Robinson et al. 1997). All histones have a Figure 1. X-Ray Structure of the nucleosome core particle; similar structure of the globular domain and unstruc- pdb code (1kx5). DNA is wrapped around two copies each tured N-terminal ‘tail’. Two dimers of H3/H4 of H2A, H2B, H3, and H4. Evaluation of post-translational modifications in histone proteins Page 3 of 29 135 Table 1. Different types of PTMs and the amino acids modified in histone proteins Residues Degree of Modification modified modification Abbreviation Functions Regulated Acetylation Lysine (K) Mono ac Transcription, replication, condensation, gene silencing, DNA repair, and cell – cycle progression (Vendone et al. 2005) Methylation Lysine (K) Mono me1 Transcription, repair (Lohrum et al. 2007;Ng Di me2 et al. 2009) Tri me3 heterochromatin formation, X-chromosome inactivation, transcriptional regulation and regulation of gene expression (Martin and Zhang 2005; Shi et al. 2012) Methylation Arginine (R) Mono me1 DNA repair, and transcription, signal transduction Di- me2s and transcriptional regulation, protein symmetric mea2s translocation, ribosomal biosynthesis and all Di- aspects of RNA metabolism (Litt et al. 2009; asymmetric Murn and Shi 2017; Wesche et al. 2017) Phosphorylation Serine (S) Mono ph Transcriptional regulation, apoptosis, cell cycle threonine (T) progression, DNA repair, chromosome tyrosine (Y) condensation, developmental gene regulation, and heat shock-induced pathways (Banerjee and Chakravarti 2011;Loet al. 2005) Ubiquitylation Lysine (K) Mono ub1 Repair, transcriptional activation and silencing (Cao and Yan 2012; Sawan and Herceg 2010) SUMOylation Lysine (K) Mono sum Replication, meiosis and mitosis, cell division, transcriptional regulation and enhancement of transcriptional activity, nuclear and protein trafficking, and the DNA