Dataset Information

Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin.

ABSTRACT: Microrchidia (MORC) proteins are GHKL (gyrase, heat-shock protein 90, histidine kinase, MutL) ATPases that function in gene regulation in multiple organisms. Animal MORCs also contain CW-type zinc finger domains, which are known to bind to modified histones. We solved the crystal structure of the murine MORC3 ATPase-CW domain bound to the nucleotide analog AMPPNP (phosphoaminophosphonic acid-adenylate ester) and in complex with a trimethylated histone H3 lysine 4 (H3K4) peptide (H3K4me3). We observed that the MORC3 N-terminal ATPase domain forms a dimer when bound to AMPPNP. We used native mass spectrometry to show that dimerization is ATP-dependent, and that dimer formation is enhanced in the presence of nonhydrolyzable ATP analogs. The CW domain uses an aromatic cage to bind trimethylated Lys4 and forms extensive hydrogen bonds with the H3 tail. We found that MORC3 localizes to promoters marked by H3K4me3 throughout the genome, consistent with its binding to H3K4me3 in vitro. Our work sheds light on aspects of the molecular dynamics and function of MORC3.

SUBMITTER: Li S

PROVIDER: S-EPMC5024608 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin.

Li Sisi S Yen Linda L Pastor William A WA Johnston Jonathan B JB Du Jiamu J Shew Colin J CJ Liu Wanlu W Ho Jamie J Stender Bryan B Clark Amander T AT Burlingame Alma L AL Daxinger Lucia L Patel Dinshaw J DJ Jacobsen Steven E SE

Proceedings of the National Academy of Sciences of the United States of America 20160815 35

Microrchidia (MORC) proteins are GHKL (gyrase, heat-shock protein 90, histidine kinase, MutL) ATPases that function in gene regulation in multiple organisms. Animal MORCs also contain CW-type zinc finger domains, which are known to bind to modified histones. We solved the crystal structure of the murine MORC3 ATPase-CW domain bound to the nucleotide analog AMPPNP (phosphoaminophosphonic acid-adenylate ester) and in complex with a trimethylated histone H3 lysine 4 (H3K4) peptide (H3K4me3). We obs ...[more]

PMID: 27528681

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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

Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin.

Publications

Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin.

Similar Datasets

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