Abstract
Regulation of gene expression includes the replacement of canonical histones for non-allelic histone variants, as well as their multiple targeting by postranslational modifications. H2A variants are highly conserved between species suggesting they execute important functions that cannot be accomplished by canonical histones. Altered expression of many H2A variants is associated to cancer. MacroH2A variants are enriched in heterocromatic foci and necessary for chromatin condensation. MacroH2A1.1 and macroH2A1.2 are two mutually exclusive isoforms. MacroH2A1.1 and macroH2A2 inhibit proliferation and are associated with better cancer prognosis; while macroH2A1.2 is associated to cancer progression. H2AX variant functions as a sensor of DNA damage and defines the cellular response towards DNA repair or apoptosis; therefore, screening approaches and therapeutic options targeting H2AX have been proposed. H2A.Z is enriched in euchromatin, acting as a proto-oncogene with established roles in hormone responsive cancers and overexpressed in endocrine-resistant disease. Other H2A family members have also been found altered in cancer, but their function remains unknown. Substantial progress has been made to understand histone H2A variants, their contribution to normal cellular function and to cancer development and progression. Yet, implementation of high resolution mass spectrometry is needed to further our knowledge on highly homologous H2A variants expression and function.
Highlights
Genomic DNA in eukaryotic cells is packaged into chromatin being the nucleosome the smallest subunit
This review focuses on H2A histone variants which are altered in cancer; describes their functions, and the methodological difficulties faced in the analysis of many members of the H2A family
Epigenetic alterations preceding cancer disease or evolving alongside progression appear related to H2A variant replacement
Summary
Genomic DNA in eukaryotic cells is packaged into chromatin being the nucleosome the smallest subunit. Nucleosomes consist of 145-147 base pairs of DNA wrapped around an octamer of core histone proteins which usually includes two molecules of each of the canonical core histones: H2A, H2B, H3 and H4. Regulation of gene expression at the nucleosome level occurs through combinatorial effects of epigenetic marks including DNA methylation, core histone posttranslational modifications (hPTMs) [5] and incorporation of diverse replacement histone variants [6]. Histone variants are distinct non-allelic forms of core histones, their expression is not restricted to the S-phase, and they are incorporated into nucleosomes through DNA replication-independent mechanisms that often involve specific histone chaperones and ATP-dependent chromatin remodelling factors [10,11,12]. Substitution of one or more of the core histones with the corresponding non-allelic variants results in differences in nucleosome stability and biochemical properties, altering chromatin structure and accessibility of transcription factors and chromatin www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget/
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