Abstract
Simple SummaryThe structural unit of chromatin is the nucleosome that is composed of DNA wrapped around a core of eight histone proteins. Histone variants can replace ‘standard’ histones at specific sites of the genome. Thus, histone variants modulate all functions in the context of chromatin, such as gene expression. Here, we provide a concise review on a group of histone variants termed macroH2A. They contain two additional domains that contribute to their increased size. We discuss how these domains mediate molecular functions in normal cells and the role of macroH2As in gene expression and cancer.The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.
Highlights
Chromatin structure is the template for transcriptional regulation and chromatin-based modifications provide the molecular basis for an epigenetic memory affecting physiologic cellular functions such as proliferation, differentiation, and cell cycle [1]
The replacement of a replication-coupled histone by its histone variants has contributed to the complexity of the epigenetic landscape and highlighted the importance of chromatin-associated protein complexes in physiological tissue homeostasis and malignant transformation
Given the apparent functional relevance of macroH2A in cancer biology, much attention has been focused on mechanisms regarding the deposition of macroH2A and its effect on the chromatin landscape
Summary
Chromatin structure is the template for transcriptional regulation and chromatin-based modifications provide the molecular basis for an epigenetic memory affecting physiologic cellular functions such as proliferation, differentiation, and cell cycle [1]. While histone variant H3.3 differs from the canonical H3 by only five amino acids, active histone marks such as mono-methylation of histone 3 lysine 4 (H3K4me), acetylation of H3K9 (H3K9ac), mono- or di-methylation of H3K36 (H3K36me1/2) are preferentially enriched on H3.3 compared to canonical H3. These changes increase transcriptional activation of H3.3 enriched loci [20]. Recurrent mutations in histones were identified within the histone fold domain by large-scale cancer genome analysis in various cancers (reviewed in [15,27]). Detection of these mutations is used for diagnostic purposes in clinical routine
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