4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
- Alice Cortesi1,5,
- Matthieu Pesant1,5,
- Shruti Sinha1,5,
- Federica Marasca1,
- Eleonora Sala1,
- Francesco Gregoretti2,
- Laura Antonelli2,
- Gennaro Oliva2,
- Chiara Chiereghin3,4,
- Giulia Soldà3,4 and
- Beatrice Bodega1
- 1Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi” (INGM), 20122, Milan, Italy;
- 2CNR Institute for High Performance Computing and Networking (ICAR), 8013, Naples, Italy;
- 3Department of Biomedical Sciences, Humanitas University, 20090, Pieve Emanuele, Milan, Italy;
- 4Humanitas Clinical and Research Center, 20089, Rozzano, Milan, Italy
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↵5 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.233288.117.
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Freely available online through the Genome Research Open Access option.
- Received December 4, 2017.
- Accepted May 13, 2019.
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/.
