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Sometimes one just isn't enough: do vertebrates contain an H2A.Z hyper-variant?

Mehta M, Kim HS, Keogh MC - J. Biol. (2010)

Bottom Line: The histone variant H2A.Z seems to be an extreme example.Multiple post-translational modifications on the protein indicate further regulation.An additional layer of complexity has now been uncovered: the vertebrate form is actually encoded by two non-allelic genes that differ by expression pattern and three amino acids.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.

ABSTRACT
How much functional specialization can one component histone confer on a single nucleosome? The histone variant H2A.Z seems to be an extreme example. Genome-wide distribution maps show non-random (and evolutionarily conserved) patterns, with localized enrichment or depletion giving a tantalizing suggestion of function. Multiple post-translational modifications on the protein indicate further regulation. An additional layer of complexity has now been uncovered: the vertebrate form is actually encoded by two non-allelic genes that differ by expression pattern and three amino acids.

Show MeSH
A simplified view of H2A.Z structure and post-translational modifications. Bars indicate the major regions of divergence between H2A.Z proteins across species (green) and between H2A.Z and H2A (blue). The relative location of the nuclear localization signal (NLS) and regions of S. cerevisiae (Sc) H2A.Z (called Htz1) that mediate contact with the Nap1 chaperone and the SWR-complex (SWR-C) ATPase complex are also shown. All H2A.Z post-translational modifications identified so far are on the relatively divergent amino and carboxyl termini, so it is unclear whether each specific modification is invariably used to regulate variant function across species. Addition of post-translational modifications generally depends on the SWR complex, indicating that each modification occurs after the variant is assembled into chromatin [3,5]. A major region of difference between H2A and H2A.Z is in the Loop 1 domain, which regulates interaction between the two H2A molecules in a nucleosome. This has led to the suggestion that nucleosome core particles can only be homotypic, containing either H2A or H2A.Z. However, hybrid nucleosomes containing H2A:H2B and H2A.Z:H2B dimers have been observed [6]. The sequence of human H2A.Z-1, including the three residues that differ in H2A.Z-2, is also indicated.
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Figure 1: A simplified view of H2A.Z structure and post-translational modifications. Bars indicate the major regions of divergence between H2A.Z proteins across species (green) and between H2A.Z and H2A (blue). The relative location of the nuclear localization signal (NLS) and regions of S. cerevisiae (Sc) H2A.Z (called Htz1) that mediate contact with the Nap1 chaperone and the SWR-complex (SWR-C) ATPase complex are also shown. All H2A.Z post-translational modifications identified so far are on the relatively divergent amino and carboxyl termini, so it is unclear whether each specific modification is invariably used to regulate variant function across species. Addition of post-translational modifications generally depends on the SWR complex, indicating that each modification occurs after the variant is assembled into chromatin [3,5]. A major region of difference between H2A and H2A.Z is in the Loop 1 domain, which regulates interaction between the two H2A molecules in a nucleosome. This has led to the suggestion that nucleosome core particles can only be homotypic, containing either H2A or H2A.Z. However, hybrid nucleosomes containing H2A:H2B and H2A.Z:H2B dimers have been observed [6]. The sequence of human H2A.Z-1, including the three residues that differ in H2A.Z-2, is also indicated.

Mentions: Histone variants are non-allelic isoforms of the canonical histones that can be assembled into nucleosomes in their place, and are thought thereby to provide the basis for regulation of biological processes that require local access to DNA. In contrast to the S-phase-coupled synthesis of the major histones (timing availability to the peak demand of genome replication), variants are generally expressed throughout the cell cycle. Histone H2A has one of the largest variant families, and includes H2A.Z, a protein that is highly conserved across eukaryotes but differs considerably from the major H2A in each species (Figure 1) [1]. H2A.Z has been ascribed a large number of roles, including most recently suppressing antisense RNAs [2] and stabilizing the association of condensin with mitotic chromosomes [3]. Although we still have a poor understanding of how the variant mediates any specific function, it is likely that differential enrichment at specific locations and distinct post-translational modifications contribute. H2A.Z at the inactive X chromosome of mammalian female cells is monoubiquitinated [4], that in budding yeast (Saccharomyces cerevisiae) is sumoylated [5], and in all tested species it is subject to multiple amino-terminal acetylations (Figure 1), primarily by the Kat5 family of acetyltransferases [1,3]. Mutation of the S. cerevisiae sumoylation sites impairs movement of DNA double-strand breaks to the nuclear periphery [5], whereas an unacetylatable allele in fission yeast (Schizosaccharomyces pombe) recapitulates many of the phenotypes of a complete deletion [3]. However, it is still unknown whether the effect of any of these modifications is direct (such as steric hindrance or charge modulation influencing the formation of higher-order structures) or indirect (such as generating sites for the recruitment of regulatory proteins).


Sometimes one just isn't enough: do vertebrates contain an H2A.Z hyper-variant?

Mehta M, Kim HS, Keogh MC - J. Biol. (2010)

A simplified view of H2A.Z structure and post-translational modifications. Bars indicate the major regions of divergence between H2A.Z proteins across species (green) and between H2A.Z and H2A (blue). The relative location of the nuclear localization signal (NLS) and regions of S. cerevisiae (Sc) H2A.Z (called Htz1) that mediate contact with the Nap1 chaperone and the SWR-complex (SWR-C) ATPase complex are also shown. All H2A.Z post-translational modifications identified so far are on the relatively divergent amino and carboxyl termini, so it is unclear whether each specific modification is invariably used to regulate variant function across species. Addition of post-translational modifications generally depends on the SWR complex, indicating that each modification occurs after the variant is assembled into chromatin [3,5]. A major region of difference between H2A and H2A.Z is in the Loop 1 domain, which regulates interaction between the two H2A molecules in a nucleosome. This has led to the suggestion that nucleosome core particles can only be homotypic, containing either H2A or H2A.Z. However, hybrid nucleosomes containing H2A:H2B and H2A.Z:H2B dimers have been observed [6]. The sequence of human H2A.Z-1, including the three residues that differ in H2A.Z-2, is also indicated.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2871525&req=5

Figure 1: A simplified view of H2A.Z structure and post-translational modifications. Bars indicate the major regions of divergence between H2A.Z proteins across species (green) and between H2A.Z and H2A (blue). The relative location of the nuclear localization signal (NLS) and regions of S. cerevisiae (Sc) H2A.Z (called Htz1) that mediate contact with the Nap1 chaperone and the SWR-complex (SWR-C) ATPase complex are also shown. All H2A.Z post-translational modifications identified so far are on the relatively divergent amino and carboxyl termini, so it is unclear whether each specific modification is invariably used to regulate variant function across species. Addition of post-translational modifications generally depends on the SWR complex, indicating that each modification occurs after the variant is assembled into chromatin [3,5]. A major region of difference between H2A and H2A.Z is in the Loop 1 domain, which regulates interaction between the two H2A molecules in a nucleosome. This has led to the suggestion that nucleosome core particles can only be homotypic, containing either H2A or H2A.Z. However, hybrid nucleosomes containing H2A:H2B and H2A.Z:H2B dimers have been observed [6]. The sequence of human H2A.Z-1, including the three residues that differ in H2A.Z-2, is also indicated.
Mentions: Histone variants are non-allelic isoforms of the canonical histones that can be assembled into nucleosomes in their place, and are thought thereby to provide the basis for regulation of biological processes that require local access to DNA. In contrast to the S-phase-coupled synthesis of the major histones (timing availability to the peak demand of genome replication), variants are generally expressed throughout the cell cycle. Histone H2A has one of the largest variant families, and includes H2A.Z, a protein that is highly conserved across eukaryotes but differs considerably from the major H2A in each species (Figure 1) [1]. H2A.Z has been ascribed a large number of roles, including most recently suppressing antisense RNAs [2] and stabilizing the association of condensin with mitotic chromosomes [3]. Although we still have a poor understanding of how the variant mediates any specific function, it is likely that differential enrichment at specific locations and distinct post-translational modifications contribute. H2A.Z at the inactive X chromosome of mammalian female cells is monoubiquitinated [4], that in budding yeast (Saccharomyces cerevisiae) is sumoylated [5], and in all tested species it is subject to multiple amino-terminal acetylations (Figure 1), primarily by the Kat5 family of acetyltransferases [1,3]. Mutation of the S. cerevisiae sumoylation sites impairs movement of DNA double-strand breaks to the nuclear periphery [5], whereas an unacetylatable allele in fission yeast (Schizosaccharomyces pombe) recapitulates many of the phenotypes of a complete deletion [3]. However, it is still unknown whether the effect of any of these modifications is direct (such as steric hindrance or charge modulation influencing the formation of higher-order structures) or indirect (such as generating sites for the recruitment of regulatory proteins).

Bottom Line: The histone variant H2A.Z seems to be an extreme example.Multiple post-translational modifications on the protein indicate further regulation.An additional layer of complexity has now been uncovered: the vertebrate form is actually encoded by two non-allelic genes that differ by expression pattern and three amino acids.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.

ABSTRACT
How much functional specialization can one component histone confer on a single nucleosome? The histone variant H2A.Z seems to be an extreme example. Genome-wide distribution maps show non-random (and evolutionarily conserved) patterns, with localized enrichment or depletion giving a tantalizing suggestion of function. Multiple post-translational modifications on the protein indicate further regulation. An additional layer of complexity has now been uncovered: the vertebrate form is actually encoded by two non-allelic genes that differ by expression pattern and three amino acids.

Show MeSH