NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins
The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumer...
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eLife Sciences Publications Ltd
2018-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/31023 |
| _version_ | 1818025010128748544 |
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| author | Amy E Campbell Sean C Shadle Sujatha Jagannathan Jong-Won Lim Rebecca Resnick Rabi Tawil Silvère M van der Maarel Stephen J Tapscott |
| author_facet | Amy E Campbell Sean C Shadle Sujatha Jagannathan Jong-Won Lim Rebecca Resnick Rabi Tawil Silvère M van der Maarel Stephen J Tapscott |
| author_sort | Amy E Campbell |
| collection | DOAJ |
| description | The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins. These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells. Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. Together, these findings identify NuRD and CAF-1 as mediators of DUX4 chromatin repression and suggest a mechanism for the amplification of DUX4 expression in FSHD muscle cells. |
| first_indexed | 2024-12-10T04:09:18Z |
| format | Article |
| id | doaj.art-487a44ffb3ba49459df8237332f93997 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:09:18Z |
| publishDate | 2018-03-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-487a44ffb3ba49459df8237332f939972022-12-22T02:02:47ZengeLife Sciences Publications LtdeLife2050-084X2018-03-01710.7554/eLife.31023NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteinsAmy E Campbell0https://orcid.org/0000-0001-6513-5836Sean C Shadle1Sujatha Jagannathan2https://orcid.org/0000-0001-9039-2631Jong-Won Lim3Rebecca Resnick4https://orcid.org/0000-0001-5804-4418Rabi Tawil5Silvère M van der Maarel6Stephen J Tapscott7https://orcid.org/0000-0002-0319-0968Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Molecular and Cellular Biology Program, University of Washington, Seattle, United StatesHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Molecular and Cellular Biology Program, University of Washington, Seattle, United States; Medical Scientist Training Program, University of Washington, Seattle, United StatesDepartment of Neurology, University of Rochester Medical Center, Rochester, United StatesDepartment of Human Genetics, Leiden University Medical Center, Leiden, NetherlandsHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Department of Neurology, University of Washington, Seattle, United StatesThe DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins. These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells. Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. Together, these findings identify NuRD and CAF-1 as mediators of DUX4 chromatin repression and suggest a mechanism for the amplification of DUX4 expression in FSHD muscle cells.https://elifesciences.org/articles/31023DUX4D4Z4NuRDCAF-1facioscapulohumeral dystrophyMBD3L |
| spellingShingle | Amy E Campbell Sean C Shadle Sujatha Jagannathan Jong-Won Lim Rebecca Resnick Rabi Tawil Silvère M van der Maarel Stephen J Tapscott NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins eLife DUX4 D4Z4 NuRD CAF-1 facioscapulohumeral dystrophy MBD3L |
| title | NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins |
| title_full | NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins |
| title_fullStr | NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins |
| title_full_unstemmed | NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins |
| title_short | NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins |
| title_sort | nurd and caf 1 mediated silencing of the d4z4 array is modulated by dux4 induced mbd3l proteins |
| topic | DUX4 D4Z4 NuRD CAF-1 facioscapulohumeral dystrophy MBD3L |
| url | https://elifesciences.org/articles/31023 |
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