Histone variants are proteins that substitute for the core canonical
histone
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 wr ...
s (
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.
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.
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
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
the most common
histone H3
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 stri ...
variants are H3.3 and centromeric H3 variant (cenH3, called also
CENPA
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 incl ...
in humans).
Well studied species specific variants include H3.1, H3.2, TS H3.4 (
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
), H3.5 (
hominids
The Hominidae (), whose members are known as the great apes or hominids (), are a taxonomic family of primates that includes eight extant species in four genera: '' Pongo'' (the Bornean, Sumatran and Tapanuli orangutan); ''Gorilla'' (the east ...
), H3.Y (
primates
Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...
).
Except for cenH3 histone, H3 variants are highly sequence conserved differing only by a few amino acids.
Histone H3.3 has been found to play an important role in maintaining genome integrity during the mammalian development.
Variants of histone H4
Histone H4
Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryote, eukaryotic cells. Featuring a main globular domain and a long N-terminus, N-terminal tail, H4 is involved with the structure of the nucleos ...
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
''Trypanosoma'' is a genus of kinetoplastids (class Trypanosomatidae), a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Sarcomastigophora. The name is derived from the Greek ''trypano-'' (bore ...
are known to have a variant of H4 named H4.V.
In
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
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.
Variants of histone H2A
Histone H2A
Histone H2A is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.
The other histone proteins are: H1, H2B, H3 and H4.
Background
Histones are proteins that package DNA into nucleosomes. Hist ...
has the highest number of known variants, some of which are relatively well characterized.
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.
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
The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health (NIH). It is approved and funded by the government of the United States. The ...
, 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.
MS_HistoneDB is a proteomics-oriented manually curated databases for mouse and human histone variants.
References
{{Reflist
External links
HistoneDB 2.0 - Database of histones and variants at
NCBI
The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health (NIH). It is approved and funded by the government of the United States. The ...
Proteins