A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression
| Autor: | Goossens, R., Tihaya, M.S., Heuvel, A. van den, Tabot-Ndip, K., Willemsen, I.M., Tapscott, S.J., Gonzalez Prieto, R., Chang, J.G., Vertegaal, A.C.O., Balog, J., Maarel, S.M. van der |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Chromosomal Proteins Non-Histone Science Article 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Humans 030304 developmental biology Homeodomain Proteins 0303 health sciences Multidisciplinary DNA Helicases Gene Expression Regulation Developmental Neuromuscular disease Muscular Dystrophy Facioscapulohumeral Chromatin Protein-protein interaction networks HEK293 Cells ATPases Associated with Diverse Cellular Activities Medicine Epigenetics Carrier Proteins 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) Scientific Reports, 11(1). NATURE PORTFOLIO Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor, which is mutated in > 95% of Facioscapulohumeral dystrophy (FSHD) type 2 cases. In FSHD2, SMCHD1 mutations ultimately result in the presence of the cleavage stage transcription factor DUX4 in muscle cells due to a failure in epigenetic repression of the D4Z4 macrosatellite repeat on chromosome 4q, which contains the DUX4 locus. While binding of SMCHD1 to D4Z4 and its necessity to maintain a repressive D4Z4 chromatin structure in somatic cells are well documented, it is unclear how SMCHD1 is recruited to D4Z4, and how it exerts its repressive properties on chromatin. Here, we employ a quantitative proteomics approach to identify and characterize novel SMCHD1 interacting proteins, and assess their functionality in D4Z4 repression. We identify 28 robust SMCHD1 nuclear interactors, of which 12 are present in D4Z4 chromatin of myocytes. We demonstrate that loss of one of these SMCHD1 interacting proteins, RuvB-like 1 (RUVBL1), further derepresses DUX4 in FSHD myocytes. We also confirm the interaction of SMCHD1 with EZH inhibitory protein (EZHIP), a protein which prevents global H3K27me3 deposition by the Polycomb repressive complex PRC2, providing novel insights into the potential function of SMCHD1 in the repression of DUX4 in the early stages of embryogenesis. The SMCHD1 interactome outlined herein can thus provide further direction into research on the potential function of SMCHD1 at genomic loci where SMCHD1 is known to act, such as D4Z4 repeats, the inactive X chromosome, autosomal gene clusters, imprinted loci and telomeres. |
| Databáze: | OpenAIRE |
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