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IFITM1 suppresses expression of human endogenous retroviruses in human embryonic stem cells.

ABSTRACT: Interferon-induced transmembrane protein 1 (IFITM1), a member of the IFITM protein family, is a component of a multimeric complex involved in the transduction of antiproliferation and cell adhesion signals. IFITM1 is thought to play a role in antiproliferation and immune surveillance, and has been shown to restrict infection by numerous viruses. It is highly expressed in human embryonic stem cells (hESCs) but its role in hESCs remains to be elucidated. In this study, knockout of IFITM1 mediated by CRISPR/Cas9 in hESCs did not affect self-renewal, pluripotency, telomerase activity or telomeres. However expression of human endogenous retroviruses (HERVs) was higher than in wild-type hESCs, and there was also a reduced level of trimethylation of histone H3 on lysine 9 at HERV loci. These data show that IFITM1 suppresses HERVs in hESCs by regulating epigenetic modifications.

SUBMITTER: Fu Y

PROVIDER: S-EPMC5537067 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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IFITM1 suppresses expression of human endogenous retroviruses in human embryonic stem cells.

Fu Yudong Y Zhou Zhongcheng Z Wang Hua H Gong Peng P Guo Renpeng R Wang Jinmiao J Lu Xinyi X Qi Feng F Liu Lin L

FEBS open bio 20170629 8

Interferon-induced transmembrane protein 1 (IFITM1), a member of the IFITM protein family, is a component of a multimeric complex involved in the transduction of antiproliferation and cell adhesion signals. IFITM1 is thought to play a role in antiproliferation and immune surveillance, and has been shown to restrict infection by numerous viruses. It is highly expressed in human embryonic stem cells (hESCs) but its role in hESCs remains to be elucidated. In this study, knockout of <i>IFITM1</i> me ...[more]

PMID: 28781951

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Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide 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, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, 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 find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.

Dataset Information

IFITM1 suppresses expression of human endogenous retroviruses in human embryonic stem cells.

Publications

IFITM1 suppresses expression of human endogenous retroviruses in human embryonic stem cells.

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