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Interplay Between Different Covalent Modifications of the Core Histone Tails

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Interplay Between Different Covalent Modifications of the Core Histone Tails Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails Yi Zhang1,3 and Danny Reinberg2,4 1Department of Biochemistry and Biophysics, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA; 2Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA In this review, we discuss recent advances made on his- vealed that there are different types of protein complexes tone methylation and its diverse functions in regulating capable of altering the chromatin, and these may act in a gene expression. Methylation of histone polypeptides physiological context to modulate DNA accessibility. might be static and might mark a gene to be or not be One family includes multiprotein complexes that utilize transcribed. However, the decision to methylate or not the energy derived from ATP hydrolysis to mobilize or methylate a specific residue in the histone polypeptides alter the structure of nucleosomes (Kingston and Narl- is an active process that requires coordination among ikar 1999; Vignali et al. 2000). The other family includes different covalent modifications occurring at the amino protein complexes that modify the histone polypeptides termini of the histone polypeptides, the histone tails. covalently, primarily within residues located at the his- Below, we summarize recent advances on histone meth- tone tails (Wu and Grunstein 2000). yltransferases, and we discuss histone methylation As an important component of the nucleosome, each within the context of other histone tail modifications. core histone is composed of a structured, three-helix do- main called the histone fold and two unstructured tails. Although the histone tails are dispensable for the forma- Histone modifications and the histone code hypothesis tion of the nucleosome, they are required for nucleo- some–nucleosome interaction (Luger et al. 1997) and for In eukaryotic cells, genes are complexed with core his- establishing transcriptionally repressive chromatin, re- tones and other chromosomal proteins in the form of ferred to as heterochromatin. Transcriptionally active chromatin. The basic repeating unit of chromatin, the chromatin within the nucleus is referred to as euchro- nucleosome, includes two copies of each of the four core matin (Grunstein et al. 1995). histones H2A, H2B, H3, and H4 wrapped by 146 bp of The core histone tails are susceptible to a variety of DNA. With the aid of additional proteins, including his- covalent modifications, including acetylation, phos- tone H1, the nucleosomes are further packaged into 30- phorylation, methylation, and ubiquitination (Fig. 1). Al- nm fibers with six nucleosomes per turn in a spiral or though these modifications have been known for many solenoid arrangement (Kornberg and Lorch 1999; Hayes years, their functions are just beginning to be revealed. and Hansen 2001). The 30-nm fiber unfolds to generate a The identification of the first nuclear histone acetyl- template for transcription, an 11-nm fiber or beads on a transferase (HAT) as a homolog of the yeast transcrip- string, by a mechanism that is not entirely clear. How- tional coactivator Gcn5p (Brownell et al. 1996) fit well ever, it is thought that unfolding involves post-transla- with an earlier observation that acetylated histones as- tional modifications, particularly acetylation, of the core sociate with transcriptionally active genes (Hebbes et al. histone amino-terminal tails. 1988). This important finding has led to an intensive The 11-nm fiber is also repressive to processes requir- study of the function of histone acetylation in transcrip- ing access of proteins to DNA. Recent studies have re- tional regulation. As a result, both biochemical and ge- netic evidence supports an important role of histone tail acetylation in transcriptional regulation. The important Corresponding authors. discoveries include: (1) Several transcriptional coactiva- 3E-MAIL [email protected]; FAX (919) 966-9673. tors such as Gcn5, p300/CBP, PCAF, TAF250, and the 4E-MAIL [email protected]; FAX (732) 235-5294. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ p160 family of nuclear receptor coactivators contain in- gad.927301. trinsic HAT activity (Sterner and Berger 2000; Roth et al. GENES & DEVELOPMENT 15:2343–2360 © 2001 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/01 $5.00; www.genesdev.org 2343 Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Zhang and Reinberg Figure 1. Sites of post-translational modi- fications on the histone tails. The modifica- tions shown include acetylation (purple), methylation (red), phosphorylation (green), and ubiquitination (orange). Note that Lys 9 in the H3 tail can be either acetylated or methylated. 2001). (2) Global transcriptional repressors, such as Sin3 ation and transcriptional regulation, and histones are and NCoR/SMRT, among others, are associated with methylated on arginine and lysine residues only, the dis- histone deacetylases (HDAC; Pazin and Kadonaga 1997; cussion will be limited to arginine and lysine methyl- Kuzmichev and Reinberg 2001). (3) The enzymatic ac- ation. tivities of HAT/HDAC are required for their transcrip- Arginine can be either mono- or dimethylated, with tional activation/repression activity (Hassig et al. 1998; the latter in symmetric or asymmetric configurations Kadosh and Struhl 1998; Kuo et al. 1998; Wang et al. (Fig. 2). The enzymes that catalyze this process have 1998). These studies collectively demonstrate that acety- been divided into two types with the type I enzyme cata- G lation of histone tails regulates gene expression by af- lyzing the formation of N -monomethylarginine and G G fecting the dynamics of chromatin structure. In general, asymmetric N ,N -dimethylarginine residues, whereas G acetylation of core histone tails correlates with opening the type II enzyme catalyzes the formation of N -mono- G G of chromatin structure to allow transcription. methylarginine and symmetric N ,NЈ -dimethylargi- In addition to acetylation, important progress has also nine residues (Fig. 2). Similar to arginine methylation, been made in the studies of other types of covalent modi- lysine methylation on the ␧-nitrogen can also occur as fications including phosphorylation of histone H3 at mono-, di-, or trimethylated forms (Fig. 2). Studies in the Ser10 (H3-S10) and methylation of histones H3 and H4. past several years have identified several RNA-associ- The studies collectively reveal a complex interplay be- ated proteins including hnRNP A1, fibrillarin, and tween the different covalent modifications occurring on nucleolin as substrates of type I protein arginine meth- the histone tails. These studies collectively support the yltransferase (PRMT), whereas the only substrate iden- histone code hypothesis (Strahl and Allis 2000). This hy- tified so far for type II PRMT is the myelin basic protein pothesis predicts that a pre-existing modification affects (Gary and Clarke 1998). subsequent modifications on histone tails and that these First described in 1964, histones have long been modifications serve as marks for the recruitment of dif- known to be substrates for methylation (Murray 1964). ferent proteins or protein complexes to regulate diverse Early studies using metabolic labeling followed by se- chromatin functions, such as gene expression, DNA rep- quencing of bulk histones have shown that several lysine lication, and chromosome segregation. Below, we review residues, including lysines 4, 9, 27, and 36 of H3 and recent progress in histone methylation and its relation- lysine 20 of H4, are preferred sites of methylation (for ship with transcriptional regulation. review, see van Holde, 1988; Strahl et al. 1999). In addi- tion, members of the protein arginine methyltransferase family can also methylate histones in vitro (Gary and Clarke 1998). However, direct evidence linking histone Protein methylation and transcriptional regulation methylation to gene activity was not available until re- Like phosphorylation, protein methylation is a covalent cently. One major obstacle in studying the function of modification commonly occurring on carboxyl groups of histone methylation is the lack of information regarding glutamate, leucine, and isoprenylated cysteine, or on the responsible enzymes. Recent demonstration that a the side-chain nitrogen atoms of lysine, arginine, and nuclear receptor coactivator-associated protein, CARM1 histidine residues (Clarke 1993). Although a number (also known as PRMT4), is a H3-specific arginine meth- of studies have indicated a role of protein methylation yltransferase and that the human homolog of the Dro- in signal transduction and RNA metabolism (Aletta et sophila heterochromatic protein Su(var)3–9, is a H3-spe- al. 1998; Gary and Clarke 1998), the precise function cific lysine methyltransferase, provided substantial evi- of protein methylation remains largely unknown. Be- dence for the involvement of histone methylation on cause the main focus of this review is histone methyl- transcriptional regulation (Chen et al. 1999a; Rea et al. 2344 GENES
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