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PMID: 22541069 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy.

Cell ·Vol. 149 ·No. 4 ·2012-05-11 ·Pages 819-31

Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y, Gabellini D

Abstract

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.

MeSH Terms
Animals CHO Cells Cells, Cultured Cricetinae DNA-Binding Proteins/metabolism Epigenesis, Genetic Histone-Lysine N-Methyltransferase Humans Molecular Sequence Data Muscle, Skeletal/metabolism,pathology Muscular Dystrophy, Facioscapulohumeral/genetics,physiopathology Myeloid-Lymphoid Leukemia Protein/metabolism Polycomb-Group Proteins RNA, Untranslated/metabolism Repressor Proteins/metabolism Response Elements Transcription Factors/metabolism
Chemicals
DNA-Binding Proteins KMT2A protein, human Polycomb-Group Proteins RNA, Untranslated Repressor Proteins Transcription Factors Myeloid-Lymphoid Leukemia Protein ASH1L protein, human Histone-Lysine N-Methyltransferase
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Cabianca Daphne S
Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Regenerative Medicine, Stem Cells, and Gene Therapy, Milan, Italy.
Casa Valentina
Bodega Beatrice
Xynos Alexandros
Ginelli Enrico
Tanaka Yujiro
Gabellini Davide
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.03.035
Published
2012-05-11
Epub
2012-00-26
Pages
819-31
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3350859
Subset
IM
Grants
European Research Council · 204279 · International
Telethon · GGP07078 · Italy
Telethon · GTB07001 · Italy
Telethon · TCR11003 · Italy
Databases
GENBANK
JQ639078
External Links
PubMed source DOI: 10.1016/j.cell.2012.03.035 PMC Full Text View journal details
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