4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
Articolo
Data di Pubblicazione:
2019
Citazione:
4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy / A. Cortesi, M. Pesant, S. Sinha, F. Marasca, E. Sala, F. Gregoretti, L. Antonelli, G. Oliva, C. Chiereghin, G. Solda, B. Bodega. - In: GENOME RESEARCH. - ISSN 1088-9051. - 29:6(2019 Jun), pp. 883-895. [10.1101/gr.233288.117]
Abstract:
Despite increasing insights in genome structure organization, the role of DNA repetitive elements, accounting for more than two thirds of the human genome, remains elusive. Facioscapulohumeral muscular dystrophy (FSHD) is associated with deletion of D4Z4 repeat array below 11 units at 4q35.2. It is known that the deletion alters chromatin structure in cis, leading to gene up-regulation. Here we show a genome-wide role of 4q-D4Z4 array in modulating gene expression via 3D nuclear contacts. We have developed an integrated strategy of 4q-D4Z4-specific 4C-seq and chromatin segmentation analyses, showing that 4q-D4Z4 3D interactome and chromatin states of interacting genes are impaired in FSHD1 condition; in particular, genes that have lost the 4q-D4Z4 interaction and with a more active chromatin state are enriched for muscle atrophy transcriptional signature. Expression level of these genes is restored by the interaction with an ectopic 4q-D4Z4 array, suggesting that the repeat directly modulates the transcription of contacted targets. Of note, the up-regulation of atrophic genes is a common feature of several FSHD1 and FSHD2 patients, indicating that we have identified a core set of deregulated genes involved in FSHD pathophysiology.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Biomarkers; Cells, Cultured; Chromatin; Chromatin Assembly and Disassembly; Ectopic Gene Expression; Epistasis, Genetic; Gene Expression Regulation; Humans; Models, Biological; Muscle Proteins; Muscular Dystrophy, Facioscapulohumeral; SKP Cullin F-Box Protein Ligases; Chromosomes, Human, Pair 4; Tandem Repeat Sequences; Transcription, Genetic
Elenco autori:
A. Cortesi, M. Pesant, S. Sinha, F. Marasca, E. Sala, F. Gregoretti, L. Antonelli, G. Oliva, C. Chiereghin, G. Solda, B. Bodega
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