DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Science Advances Année : 2024

DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis

Eden Engal
Aveksha Sharma
Shiri Jaffe-Herman
Ophir Geminder
Gillian Kay
Marc Gotkine
Maayan Salton
Yotam Drier

Résumé

Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) is a noncanonical SMC protein and an epigenetic regulator. Mutations in SMCHD1 cause facioscapulohumeral muscular dystrophy (FSHD), by overexpressing DUX4 in muscle cells. Here, we demonstrate that SMCHD1 is a key regulator of alternative splicing in various cell types. We show how SMCHD1 loss causes splicing alterations of DNMT3B, which can lead to hypomethylation and DUX4 overexpression. Analyzing RNA sequencing data from muscle biopsies of patients with FSHD and Smchd1 knocked out cells, we found mis-splicing of hundreds of genes upon SMCHD1 loss. We conducted a high-throughput screen of splicing factors, revealing the involvement of the splicing factor RBM5 in the mis-splicing of DNMT3B. Subsequent RNA immunoprecipitation experiments confirmed that SMCHD1 is required for RBM5 recruitment. Last, we show that mis-splicing of DNMT3B leads to hypomethylation of the D4Z4 region and to DUX4 overexpression. These results suggest that DNMT3B mis-splicing due to SMCHD1 loss plays a major role in FSHD pathogenesis.
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hal-04603956 , version 1 (06-06-2024)

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Eden Engal, Aveksha Sharma, Uria Aviel, Nadeen Taqatqa, Sarah Juster, et al.. DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis. Science Advances , 2024, 10 (22), pp.eadn7732. ⟨10.1126/sciadv.adn7732⟩. ⟨hal-04603956⟩
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