RT Journal
A1 Cortesi, Alice
A1 Pesant, Matthieu
A1 Sinha, Shruti
A1 Marasca, Federica
A1 Sala, Eleonora
A1 Gregoretti, Francesco
A1 Antonelli, Laura
A1 Oliva, Gennaro
A1 Chiereghin, Chiara
A1 Soldà, Giulia
A1 Bodega, Beatrice
T1 4q-D4Z4 chromatin architecture regulates the transcription of muscle atrophic genes in facioscapulohumeral muscular dystrophy
JF Genome Research 
JO Genome Research 
YR 2019 
FD June 01 
VO 29 
IS 6 
SP 883 
OP 895 
DO 10.1101/gr.233288.117 
UL http://genome.cshlp.org/content/29/6/883.abstract 
AB 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.