Abstract
Epigenetic regulation is a crucial component of DNA maintenance and cellular identity. As our understanding of the vast array of proteins that contribute to chromatin accessibility has advanced, the role of epigenetic remodelers in disease has become more apparent. G9a is a histone methyltransferase that contributes to immune cell differentiation and function, neuronal development, and has been implicated in diseases, including cancer. In melanoma, recurrent mutations and amplifications of G9a have led to its identification as a therapeutic target. The pathways that are regulated by G9a provide an insight into relevant biomarkers for patient stratification. Future work is aided by the breadth of literature on G9a function during normal differentiation and development, along with similarities to EZH2, another histone methyltransferase that forms a synthetic lethal relationship with members of the SWI/SNF complex in certain cancers. Here, we review the literature on G9a, its role in melanoma, and lessons from EZH2 inhibitor studies.
Highlights
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While there is some evidence that G9a may facilitate the trimethylation of H3K9, the histone methyltransferase SETDB1 is critical for maintaining the DNA methylation of retrotransposons through H3K9me3 [5], while SUV39H1 and SUV39H2 deposit the trimethylation of H3K9 at constitutive heterochromatins [6]
Proteins that interact with G9a, including JARID2, contribute to normal differentiation of additional immune cells, such as invariant natural killer T cells that are derived from CD4/CD8 double-positive T cells [20]
Summary
While DNA encodes all the necessary genes, the reversible modifications to DNA and histone complexes allows for one individual to undergo development from a zygote to a complex multi-cellular organism. While there is some evidence that G9a may facilitate the trimethylation of H3K9, the histone methyltransferase SETDB1 is critical for maintaining the DNA methylation of retrotransposons through H3K9me3 [5], while SUV39H1 and SUV39H2 deposit the trimethylation of H3K9 at constitutive heterochromatins [6]. This means that G9a directly contributes to repressive dimethylation and subsequent trimethylation at H3K9 throughout the genome. Get9haylcaatne amdedtihtiyolnaatel nadond-ihtiiosntoanlenporno-theiisntsonine cpormotpelienxs winitchoGmLpPl,eoxrwaliothneG, LmPo,dourlaatlionngep, rmotoedinuslaitnicnlgudpirnogteWinIsZi,nabcliunding WpaIrZtn, earboinf dGi9nag; pHaIrFt-n1earlpohf aG,9bal;oHckIiFn-g1atlhpehtar,abnlsoccrkipintigonthaectrivanitsycroifphtiyopnoaxcitaivtaitrygeotf gheynpeosx;ipa5t3a,ragektegyetnuems;opr5s3u,papkresysotur;maonrdsHupDpAreCs1soarn;danDdMHNDTA1,Ca1haisntdonDeMdeNaTce1t,yalahsiestaonnde DdeNaAcetmyleatsheylatnradnDsfNerAasem, erethspyeltcrtaivneslfyer[a8s–e1,0r]e.sTpheectnivuemlybe[8r–o1f0G].9TahtearnguemtsbaenrdoiftsGr9eaprteasrsgievtes raonlde itns greepnreeessxipvreersoslieoninbgoetnhedeixrepcrtelsysiaonndbiontdhirdeicrtelcytlsyhaonwdciansdeirthecetliymsphaocwt tchaasteethpeigiemnpeaticct rthegaut leaptiogresnceatnichraevgeuloantoarsceclal.n have on a cell
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