Histone variants

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Histone variants are proteins that substitute for the core canonical histones (H3, H4, H2A, H2B) in nucleosomes in eukaryotes and often confer specific structural and functional features. The term might also include a set of linker histone (H1) variants, which lack a distinct canonical isoform. The differences between the core canonical histones and their variants can be summarized as follows: (1) canonical histones are replication-dependent and are expressed during the S-phase of cell cycle whereas histone variants are replication-independent and are expressed during the whole cell cycle; (2) in animals, the genes encoding canonical histones are typically clustered along the chromosome, are present in multiple copies and are among the most conserved proteins known, whereas histone variants are often single-copy genes and show high degree of variation among species; (3) canonical histone genes lack introns and use a stem loop structure at the 3’ end of their mRNA, whereas histone variant genes may have introns and their mRNA tail is usually polyadenylated. Complex multicellular organisms typically have a large number of histone variants providing a variety of different functions. Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development.

Contents

Histone variants nomenclature

Different names historically assigned to homologous proteins in different species complicate the nomenclature of histone variants. A recently suggested unified nomenclature of histone variants follows phylogeny-based approach to naming the variants. [1] According to this nomenclature, letter suffixes or prefixes are mainly used to denote structurally distinct monophyletic clades of a histone family (e.g. H2A.Z, H2B.W, subH2B). Number suffixes are assumed to be species-specific (e.g. H1.1), but are encouraged to be used consistently between species where unique orthologies are clear. However, due to historical reasons naming of certain variants may still deviate from these rules.

Variants of histone H3

Throughout eukaryotes the most common histone H3 variants are H3.3 and centromeric H3 variant (cenH3, called also CENPA in humans). [2] Well studied species specific variants include H3.1, H3.2, TS H3.4 (mammals), H3.5 (hominids), H3.Y (primates). [2] Except for cenH3 histone, H3 variants are highly sequence conserved differing only by a few amino acids. [3] [4] Histone H3.3 has been found to play an important role in maintaining genome integrity during the mammalian development. [5]

Variants of histone H4

Histone H4 is one of the slowest evolving proteins with no functional variants in the majority of species. The reason for a lack of sequence variants remains unclear. Trypanosoma are known to have a variant of H4 named H4.V. [1] In Drosophila there are H4 replacement genes that are constitutively expressed throughout the cell cycle that encode proteins that are identical in sequence to the major H4. [6]

Variants of histone H2A

Histone H2A has the highest number of known variants, some of which are relatively well characterized. [2] [7] [8] H2A.X is the most common H2A variant, with the defining sequence motif ‘SQ(E/D)Φ’ (where Φ-represents a hydrophobic residue, usually Tyr in mammals). It becomes phosphorylated during the DNA damage response, chromatin remodeling, and X-chromosome inactivation in somatic cells. H2A.X and canonical H2A have diverged several times in phylogenetic history, but each H2A.X version is characterized by similar structure and function, suggesting it may represent the ancestral state. H2A.Z regulates transcription, DNA repair, suppression of antisense RNA, and RNA Polymerase II recruitment. Notable features of H2A.Z include a sequence motif ‘DEELD,’ a one amino acid insertion in L1-loop, and a one amino acid deletion in the docking domain relative to canonical H2A. Variant H2A.Z.2 was suggested to be driving the progression of malignant melanoma. Canonical H2A can be exchanged in nucleosomes for H2A.Z with special remodeling enzymes. macroH2A contains a histone fold domain and an extra, long C-terminal macro domain which can bind poly-ADP-ribose. This histone variant is used in X-inactivation and transcriptional regulation. Structures of both domains are available, but the inter-domain linker is too flexible to be crystallized. H2A.B (Barr body deficient variant) is a rapidly evolving mammal specific variant, known for its involvement in spermatogenesis. H2A.B has a shortened docking domain, which wraps around a short DNA region. H2A.L and H2A.P variants are closely related to H2A.B, but are less studied. H2A.W is a plant specific variant with SPKK motifs at the N-terminus with a putative minor-groove-binding activity. H2A.1 is a mammalian testis, oocyte and zygote specific variant. It can preferentially dimerize with H2B.1. It is so far characterized only in mouse, but a similar gene in human is available which is located at the end of the largest histone gene cluster. Currently other less extensively studied H2A variants are starting to emerge such as H2A.J.

Variants of histone H2B

H2B histone type is known to have a limited number of variants at least in mammals, apicomplexa and sea urchins. [1] [2] [7] [8] H2B.1 is a testis, oocyte and zygote specific variant that forms subnucleosomal particles, at least, in spermatids. It can dimerize with H2A.L and H2A.1. H2B.W is involved in spermatogenesis, telomere associated functions in sperm and is found in spermatogenic cells. It is characterized by the extension of the N-terminal tail. subH2B participates in regulation of spermiogenesis and is found in non-nucleosomal particle in the subacrosome of spermatozoa. This variant has a bipartite nuclear localization signal. H2B.Z is an apicomplexan specific variant that is known to interact with H2A.Z. ‘sperm H2B’ is a putative group that contains sperm H2B histones from sea and sand urchins and potentially is common for Echinacea. Recently discovered variant H2B.E is involved in the regulation of olfactory neuron function in mice.

Databases and resources

"HistoneDB 2.0 - with variants", a database of histones and their variants maintained by National Center for Biotechnology Information, currently serves as the most comprehensive manually curated resource on histones and their variants that follows the new unified phylogeny-based nomenclature of histone variants. "Histome: The Histone Infobase" is manually curated database of histone variants in humans and associated post-translational modifications as well as modifying enzymes. [9] MS_HistoneDB is a proteomics-oriented manually curated databases for mouse and human histone variants. [10]

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

A histone fold is a structurally conserved motif found near the C-terminus in every core histone sequence in a histone octamer responsible for the binding of histones into heterodimers.

<span class="mw-page-title-main">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

HMGN proteins are members of the broader class of high mobility group (HMG) chromosomal proteins that are involved in regulation of transcription, replication, recombination, and DNA repair.

<span class="mw-page-title-main">Histone H1</span> Components of chromatin in eukaryotic cells

Histone H1 is one of the five main histone protein families which are components of chromatin in eukaryotic cells. Though highly conserved, it is nevertheless the most variable histone in sequence across species.

<span class="mw-page-title-main">Histone H3</span> One of the five main histone proteins

Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.

<span class="mw-page-title-main">Histone H4</span> One of the five main histone proteins involved in the structure of chromatin

Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.

<span class="mw-page-title-main">Histone H2A</span> One of the five main histone proteins

Histone H2A is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.

Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and long N-terminal and C-terminal tails, H2B is involved with the structure of the nucleosomes.

<span class="mw-page-title-main">CENPA</span>

Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene. CENPA is a histone H3 variant which is the critical factor determining the kinetochore position(s) on each chromosome in most eukaryotes including humans.

Histone H2A.Z is a protein that in humans is encoded by the H2AZ1 gene.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones. The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. The H2AFZ gene encodes a replication-independent member of the histone H2A family that is distinct from other members of the family. Studies in mice have shown that this particular histone is required for embryonic development and indicate that lack of functional histone H2A leads to embryonic lethality.

<span class="mw-page-title-main">HMGN2</span> Protein-coding gene in the species Homo sapiens

Non-histone chromosomal protein HMG-17 is a protein that in humans is encoded by the HMGN2 gene.

<span class="mw-page-title-main">JADE1</span> Protein-coding gene in the species Homo sapiens

JADE1 is a protein that in humans is encoded by the JADE1 gene.

<span class="mw-page-title-main">HIST1H1T</span>

Histone H1t is a protein that in humans is encoded by the HIST1H1T gene.

High mobility group protein HMG14 and HMG17 also known as nucleosomal binding domain is a family of evolutionarily related proteins.

<span class="mw-page-title-main">Nucleic acid quaternary structure</span>

Nucleic acidquaternary structure refers to the interactions between separate nucleic acid molecules, or between nucleic acid molecules and proteins. The concept is analogous to protein quaternary structure, but as the analogy is not perfect, the term is used to refer to a number of different concepts in nucleic acids and is less commonly encountered. Similarly other biomolecules such as proteins, nucleic acids have four levels of structural arrangement: primary, secondary, tertiary, and quaternary structure. Primary structure is the linear sequence of nucleotides, secondary structure involves small local folding motifs, and tertiary structure is the 3D folded shape of nucleic acid molecule. In general, quaternary structure refers to 3D interactions between multiple subunits. In the case of nucleic acids, quaternary structure refers to interactions between multiple nucleic acid molecules or between nucleic acids and proteins. Nucleic acid quaternary structure is important for understanding DNA, RNA, and gene expression because quaternary structure can impact function. For example, when DNA is packed into chromatin, therefore exhibiting a type of quaternary structure, gene transcription will be inhibited.

<span class="mw-page-title-main">Nuclear organization</span> Spatial distribution of chromatin within a cell nucleus

Nuclear organization refers to the spatial distribution of chromatin within a cell nucleus. There are many different levels and scales of nuclear organisation. Chromatin is a higher order structure of DNA.

<span class="mw-page-title-main">Linker histone H1 variants</span>

The linker histone H1 is a protein family forming a critical component of eukaryotic chromatin. H1 histones bind to the linker DNA exiting from the nucleosome core particle, while the core histones form the octamer core of the nucleosome around which the DNA is wrapped.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

The Histone Database is a comprehensive database of histone protein sequences including histone variants, classified by histone types and variants, maintained by National Center for Biotechnology Information. The creation of the Histone Database was stimulated by the X-ray analysis of the structure of the nucleosomal core histone octamer followed by the application of a novel motif searching method to a group of proteins containing the histone fold motif in the early-mid-1990. The first version of the Histone Database was released in 1995 and several updates have been released since then.

References

  1. 1 2 3 Talbert PB, Ahmad K, Almouzni G, Ausio J, Berger F, Bhalla PL, Bonner WM, Cande WZ, Chadwick BP, Chan SW, Cross GA, Cui L, Dimitrov SI, Doenecke D, Eirin-Lopez JM, Gorovsky MA, Hake SB, Hamkalo BA, Holec S, Jacobsen SE, Kamieniarz K, Khochbin S, Ladurner AG, Landsman D, Latham JA, Loppin B, Malik HS, Marzluff WF, Pehrson JR, Postberg J, Schneider R, Singh MB, Smith MM, Thompson E, Torres-Padilla ME, Tremethick DJ, Turner BM, Waterborg JH, Wollmann H, Yelagandula R, Zhu B, Henikoff S (12 April 2012). "A unified phylogeny-based nomenclature for histone variants". Epigenetics & Chromatin . 5:7: 7. doi:10.1186/1756-8935-5-7. PMC   3380720 . PMID   22650316.
  2. 1 2 3 4 "Histone Variants Database 2.0". National Center for Biotechnology Information . Retrieved 13 January 2017.
  3. ↑ Marzluff WF, Gongidi P, Woods KR, Jin J, Maltais LJ (Nov 2002). "The human and mouse replication-dependent histone genes". Genomics. 80 (5): 487–98. doi:10.1016/S0888-7543(02)96850-3. PMID   12408966.
  4. ↑ Hake SB, Garcia BA, Duncan EM, Kauer M, Dellaire G, Shabanowitz J, Bazett-Jones DP, Allis CD, Hunt DF (Jan 2006). "Expression patterns and post-translational modifications associated with mammalian histone H3 variants". The Journal of Biological Chemistry. 281 (1): 559–68. doi: 10.1074/jbc.M509266200 . PMID   16267050.
  5. ↑ Jang CW, Shibata Y, Starmer J, Yee D, Magnuson T (Jul 2015). "Histone H3.3 maintains genome integrity during mammalian development". Genes & Development. 29 (13): 1377–92. doi:10.1101/gad.264150.115. PMC   4511213 . PMID   26159997.
  6. ↑ Kamakaka, Biggins (2005). "Histone variants: deviants?". Genes Dev. 19 (3): 295–316. doi: 10.1101/gad.1272805 . PMID   15687254.
  7. 1 2 Draizen EJ, Shaytan AK, Marino-Ramirez L, Talbert PB, Landsman D, Panchenko AR (2016). "HistoneDB 2.0: a histone database with variants--an integrated resource to explore histones and their variants". Database: The Journal of Biological Databases and Curation. 2016: baw014. doi:10.1093/database/baw014. PMC   4795928 . PMID   26989147.
  8. 1 2 Shaytan AK, Landsman D, Panchenko AR (2015). "Nucleosome adaptability conferred by sequence and structural variations in histone H2A-H2B dimers". Current Opinion in Structural Biology. 32: 48–57. doi:10.1016/j.sbi.2015.02.004. PMC   4512853 . PMID   25731851.
  9. ↑ "Histome: The Histone Infobase" . Retrieved 13 January 2017.
  10. ↑ El Kennani S, Adrait A, Shaytan AK, Khochbin S, Bruley C, Panchenko AR, Landsman D, Pflieger D, Govin J (2017). "MS_HistoneDB, a manually curated resource for proteomic analysis of human and mouse histones". Epigenetics Chromatin. 10: 2. doi:10.1186/s13072-016-0109-x. PMC   5223428 . PMID   28096900.
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