The role of MORC3 in silencing transposable elements in mouse embryonic stem cells

作者：Varsha P. Desai, Jihed Chouaref, Haoyu Wu, William A. Pastor, Ryan L. Kan, Harald Oey, Zheng Li, Jamie Ho, Kelly K. D. Vonk, David San León, Michael A. Christopher, Amander T. Clark, Steven E. Jacobsen, Lucia Daxinger · 发表于：Epigenetics & Chromatin · 年份：2021 · DOI：10.1186/s13072-021-00420-9 · 被引用次数：33 · 研究领域：Chromosomal and Genetic Variations、Genomics and Rare Diseases、Genomics and Chromatin Dynamics

BACKGROUND: Microrchidia proteins (MORCs) are involved in epigenetic gene silencing in a variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mammalian MORC3 mutations are associated with immune system defects and human cancers such as bladder, uterine, stomach, lung, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. RESULTS: In this study, we identified that mutation in Morc3 results in a suppressor of variegation phenotype in a Modifiers of murine metastable epialleles Dominant (MommeD) screen. We also find that MORC3 functions as an epigenetic silencer of transposable elements (TEs) in mouse embryonic stem cells (mESCs). Loss of Morc3 results in upregulation of TEs, specifically those belonging to the LTR class of retrotransposons also referred to as endogenous retroviruses (ERVs). Using ChIP-seq we found that MORC3, in addition to its known localization at H3K4me3 sites, also binds to ERVs, suggesting a direct role in regulating their expression. Previous studies have shown that these ERVs are marked by the repressive histone mark H3K9me3 which plays a key role in their silencing. However, we found that levels of H3K9me3 showed only ...