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A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy

Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leadi...

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Autores principales: Cabianca, Daphne S., Casa, Valentina, Bodega, Beatrice, Xynos, Alexandros, Ginelli, Enrico, Tanaka, Yujiro, Gabellini, Davide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350859/
https://www.ncbi.nlm.nih.gov/pubmed/22541069
http://dx.doi.org/10.1016/j.cell.2012.03.035
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author Cabianca, Daphne S.
Casa, Valentina
Bodega, Beatrice
Xynos, Alexandros
Ginelli, Enrico
Tanaka, Yujiro
Gabellini, Davide
author_facet Cabianca, Daphne S.
Casa, Valentina
Bodega, Beatrice
Xynos, Alexandros
Ginelli, Enrico
Tanaka, Yujiro
Gabellini, Davide
author_sort Cabianca, Daphne S.
collection PubMed
description Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de-repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and that D4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin-associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease.
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spelling pubmed-33508592012-05-18 A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy Cabianca, Daphne S. Casa, Valentina Bodega, Beatrice Xynos, Alexandros Ginelli, Enrico Tanaka, Yujiro Gabellini, Davide Cell Article Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de-repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and that D4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin-associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease. Cell Press 2012-05-11 /pmc/articles/PMC3350859/ /pubmed/22541069 http://dx.doi.org/10.1016/j.cell.2012.03.035 Text en © 2012 ELL & Excerpta Medica. https://creativecommons.org/licenses/by-nc-nd/3.0/ Open Access under CC BY-NC-ND 3.0 (https://creativecommons.org/licenses/by-nc-nd/3.0/) license
spellingShingle Article
Cabianca, Daphne S.
Casa, Valentina
Bodega, Beatrice
Xynos, Alexandros
Ginelli, Enrico
Tanaka, Yujiro
Gabellini, Davide
A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
title A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
title_full A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
title_fullStr A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
title_full_unstemmed A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
title_short A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
title_sort long ncrna links copy number variation to a polycomb/trithorax epigenetic switch in fshd muscular dystrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350859/
https://www.ncbi.nlm.nih.gov/pubmed/22541069
http://dx.doi.org/10.1016/j.cell.2012.03.035
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