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4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy

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...

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Autores principales: Cortesi, Alice, Pesant, Matthieu, Sinha, Shruti, Marasca, Federica, Sala, Eleonora, Gregoretti, Francesco, Antonelli, Laura, Oliva, Gennaro, Chiereghin, Chiara, Soldà, Giulia, Bodega, Beatrice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581056/
https://www.ncbi.nlm.nih.gov/pubmed/31097473
http://dx.doi.org/10.1101/gr.233288.117
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author Cortesi, Alice
Pesant, Matthieu
Sinha, Shruti
Marasca, Federica
Sala, Eleonora
Gregoretti, Francesco
Antonelli, Laura
Oliva, Gennaro
Chiereghin, Chiara
Soldà, Giulia
Bodega, Beatrice
author_facet Cortesi, Alice
Pesant, Matthieu
Sinha, Shruti
Marasca, Federica
Sala, Eleonora
Gregoretti, Francesco
Antonelli, Laura
Oliva, Gennaro
Chiereghin, Chiara
Soldà, Giulia
Bodega, Beatrice
author_sort Cortesi, Alice
collection PubMed
description 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.
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spelling pubmed-65810562019-07-02 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy Cortesi, Alice Pesant, Matthieu Sinha, Shruti Marasca, Federica Sala, Eleonora Gregoretti, Francesco Antonelli, Laura Oliva, Gennaro Chiereghin, Chiara Soldà, Giulia Bodega, Beatrice Genome Res Research 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. Cold Spring Harbor Laboratory Press 2019-06 /pmc/articles/PMC6581056/ /pubmed/31097473 http://dx.doi.org/10.1101/gr.233288.117 Text en © 2019 Cortesi et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Cortesi, Alice
Pesant, Matthieu
Sinha, Shruti
Marasca, Federica
Sala, Eleonora
Gregoretti, Francesco
Antonelli, Laura
Oliva, Gennaro
Chiereghin, Chiara
Soldà, Giulia
Bodega, Beatrice
4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
title 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
title_full 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
title_fullStr 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
title_full_unstemmed 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
title_short 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
title_sort 4q-d4z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581056/
https://www.ncbi.nlm.nih.gov/pubmed/31097473
http://dx.doi.org/10.1101/gr.233288.117
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