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The Role of Macroh2a Histone Variants in Cancer

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The Role of Macroh2a Histone Variants in Cancer cancers Review The Role of MacroH2A Histone Variants in Cancer Chen-Jen Hsu 1, Oliver Meers 2 , Marcus Buschbeck 2,3,* and Florian H. Heidel 1,4,* 1 Internal Medicine C, Greifswald University Medicine, 17475 Greifswald, Germany; [email protected] 2 Cancer and Leukaemia Epigenetics and Biology Program, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] 3 Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Campus Can Ruti, 08916 Badalona, Spain 4 Leibniz Institute on Aging, Fritz-Lipmann Institute, 07745 Jena, Germany * Correspondence: [email protected] (M.B.); fl[email protected] (F.H.H.); Tel.: +34-935-572-800 (M.B.); +49-383-486-6698 (F.H.H.); Fax: +49-383-486-6713 (F.H.H.) Simple Summary: The 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. Abstract: 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 Citation: Hsu, C.-J.; Meers, O.; Buschbeck, M.; Heidel, F.H. The Role differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of MacroH2A Histone Variants in of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular Cancer. Cancers 2021, 13, 3003. in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a https://doi.org/10.3390/ globular macrodomain. We discuss how these domains mediate different molecular functions related cancers13123003 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, Academic Editor: Aamir Ahmad 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 Received: 12 May 2021 development and progression. Accepted: 14 June 2021 Published: 15 June 2021 Keywords: macroH2A; histone variants; epigenetics; chromatin; cancer; macrodomain; tumor suppressor; oncohistone; malignant transformation Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction 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]. In cells, only Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. a small fraction of the 6 billion DNA bases comprising the genome is accessible to the This article is an open access article transcriptional machinery. The remainder is compacted and sequestered by hierarchical distributed under the terms and folding of DNA into compacted chromatin. The configuration of chromatin, including conditions of the Creative Commons nucleosome positioning and three-dimensional folding, has an impact on the accessibility Attribution (CC BY) license (https:// of DNA for transcription factor binding [2]. The regulation of chromatin structure occurs creativecommons.org/licenses/by/ on multiple levels and contributes to correct temporal and spatial transcriptional programs 4.0/). that are essential for cell identity in the organism. Disruption of chromatin homeostasis is Cancers 2021, 13, 3003. https://doi.org/10.3390/cancers13123003 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3003 2 of 16 Cancers 2021, 13, 3003 2 of 16 programs that are essential for cell identity in the organism. Disruption of chromatin ho- meostasis is a hallmark of cancer and often promotes oncogenic gene expression. Target- inga hallmarkof cancer-associated of cancer and epigenetic often promotes changes oncogenic has already gene expression. been successful Targeting for oftherapeutic cancer- intervention.associated epigenetic Epigenetic changes modulators has already called been ‘epi-drugs’ successful (e.g., for inhibitors therapeutic ofintervention. DNA methyl- transferasesEpigenetic modulatorsand histone called deacetylases) ‘epi-drugs’ have (e.g., been inhibitors approved of DNA for the methyltransferases treatment of different and cancershistone [3–5]. deacetylases) Furthermore, have beenepigenetic approved mark fors themay treatment serve as ofbiomarkers different cancers for diagnosis, [3–5]. prognosisFurthermore, and prediction epigenetic of marks disease may recurrence serve as biomarkers [6,7]. for diagnosis, prognosis and prediction of disease recurrence [6,7]. The structural unit of chromatin is the nucleosome. In eukaryotic cells, the nucleo- The structural unit of chromatin is the nucleosome. In eukaryotic cells, the nucleosome some consists of approximately 147 base pairs of genomic DNA wrapped around an oc- consists of approximately 147 base pairs of genomic DNA wrapped around an octameric tamericcore of core histones of histones H2A, H2B,H2A, H3 H2B, and H3 H4 and [8, 9H4]. The[8,9]. nucleosome The nucleosome is further is further stabilized stabilized by bythe the binding binding of of linker linker histone histone H1 H1 bound bound at at the the entry entry and and exit exit sites sites of theof the DNA DNA [10 ].[10]. The The N-terminalN-terminal tails tails of of all core histoneshistones and and the the C-terminal C-terminal tail tail of H2Aof H2A histones histones protrude protrude out of out ofthe the complex complex structure structure of theof the nucleosome. nucleosome. Post-translational Post-translational modification modification (PTM) (PTM) of histone of his- tonetails tails bookmarks bookmarks the genome. the genome. Together Together with DNA with methylation, DNA methylation, they provide they anprovide important an im- portantpart of epigeneticpart of epigenetic memory regardingmemory transcriptionalregarding transcriptional events [11,12 ].events Epigenetic [11,12]. mechanisms Epigenetic mechanismsare shown in are Figure shown1. in Figure 1. FigureFigure 1. Schematic 1. Schematic representation representation of of epigenet epigeneticic mechanisms mechanisms including histonehistonetail tail modification, modification, histone histone variant variant replace- replace- ment,ment, DNA DNA methylation methylation and and non-coding non-coding RNA-based RNA-based mechanisms. WhileWhile DNA DNA methylation methylation and histone modificationsmodifications have have been been studied studied in in detail, detail, the the functional consequences of replacing replication-coupled histones with variant histone functional consequences of replacing replication-coupled histones with variant histone proteins is less well understood. Histones contribute to DNA template-based regulation of proteins is less well understood. Histones contribute to DNA template-based regulation the genome. In mammals, replication-coupled histones are encoded by multiple intron-less ofgene the genome. clusters throughoutIn mammals, the replication-coupled genome, synthesized histones exclusively are encoded in the S by phase multiple of the intron- cell lesscycle, gene and clusters packaged throughout into newly the replicated genome, DNA synthesized [13]. In contrast, exclusively individual in the genes S phase encode of the cellvariant cycle, histone and packaged proteins that into are newly expressed replicat anded incorporated DNA [13]. into In chromatincontrast, independentindividual genes of encodereplication. variant Each histone histone proteins variant that has aare unique expr temporalessed and expression, incorporated and into their chromatin locus-specific inde- pendentincorporation of replication. is mediated Each by histone dedicated variant histone has chaperonesa unique temporal and chromatin expression, remodelers. and their locus-specificTherefore, histone incorporation variants areis mediated likely to fulfillby dedicated specific histone cellular chaperones functions that and cannot chromatin be remodelers.substituted Therefore, by replication-coupled histone variants histones are [14likely]. to fulfill specific cellular functions that cannotHistone be substituted variants by differ replication-coupled from replication-coupled histones [14]. histones. These differences may rangeHistone from exchangevariants ofdiffer single from amino replicatio acids ton-coupled the inclusion histones. of additional These differences domains [15 may]. rangeThus, from histone exchange variants of can single mediate amino specific acids molecular to the inclusion functions of in aadditional locus-specific domains manner. [15]. Thus,Differences
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