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Identification of SMCHD1 as a Novel Regulator of Alternative Splicing in FSHD2

ABSTRACT: Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) is a non-canonical member of the structural maintenance of chromosomes (SMC) protein family involved in the regulation of chromatin structure, epigenetic regulation and transcription. Mutations in SMCHD1 cause facioscapulohumeral muscular dystrophy type 2 (FSHD2), a rare genetic disorder characterized by progressive muscle weakness and wasting, believed to be caused by aberrant expression of DUX4 in muscle cells. Here we suggest a new role for SMCHD1 as a regulator of alternative splicing, and demonstrate how splicing alteration caused by SMCHD1 mutations lead to DUX4 expression and FSHD pathogenesis. Analyzing RNA-seq data from muscle biopsies of FSHD2 patients and FSHD2 mouse model found that hundreds of genes were alternatively spliced upon SMCHD1 mutation. At least 20% of alternatively spliced genes were associated with abnormalities of the musculature. Moreover, we show that alternatively spliced exons tend to be bound by SMCHD1, and SMCHD1 bound exons demonstrate slower elongation rate, suggesting SMCHD1 binding promotes exon exclusion by slowing RNAPII. Specifically, we discovered that SMCHD1 mutations promotes the splicing of the DNMT3B1 isoform of DNMT3B, which leads to hypomethylation of the D4Z4 region and DUX4 expression. These results suggest that alternative splicing regulated by SMCHD1 may play a major role in FSHD2 pathogenesis by promoting alternative splicing of different targets including DNMT3B, and highlight the potential for targeting alternative splicing as a therapeutic strategy for this disorder.

ORGANISM(S): Mus musculus

PROVIDER: GSE223039 | GEO | 2024/04/13

REPOSITORIES: GEO

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Project description:T cell activation leads to dramatic changes in cellular phenotype. We used CD3/CD28-activated human CD4 T cells to study how RNA binding proteins define the post-transcriptional landscape. Using RIPseq, we identified the RNA interactome of U2AF2 and show at the global level that U2AF2 binds the majority of transcripts that are differentially expressed and/or alternatively spliced during CD4 T cell activation. A unique protein interactome centered on U2AF2 is assembled in response to activation. Knocking down specific U2AF2 interacting partners (U2AF1, SYNCRIP, SRRM2, ILF2) selectively affects cytokine secretion and expression of activation markers. Furthermore, the expression and/or alternative splicing of transcripts important for immune cell function are also affected by knocking down these U2AF2 interacting proteins. U2AF1 and SYNCRIP knockdowns affect the proteins and transcripts bound to U2AF2, altering the transcriptome. Our work highlights the importance of RNA binding protein complexes in regulating the differential expression and alternative splicing that defines T cell activation. HTA 2.0 microarray results of total from a primary CD4 T cell culture after treatment with siRNAs (Control, U2AF1, SRRM2, SYNCRIP, and ILF2) and 24 hours after anti-CD3/CD28 bead activation Please note that the Series supplementary 'TotalRNA_HTA2_all_siRNA_100414.xslx' file has multiple worksheets containing: 1) Differentially expressed genes in ctrl siRNA vs. U2AF1 siRNA; 2) Differntially spliced genes in ctrl siRNA vs. U2AF1 siRNA; 3) Differentially spliced exons in ctrl siRNA vs. U2AF1 siRNA; 4) Differentially expressed genes in ctrl siRNA vs. SRRM2 siRNA; 5) Differntially spliced genes in ctrl siRNA vs. SRRM2 siRNA; 6) Differentially spliced exons in ctrl siRNA vs. SRRM2 siRNA; 7) Differentially expressed genes in ctrl siRNA vs. SYNCRIP siRNA; 8) Differntially spliced genes in ctrl siRNA vs. SYNCRIP siRNA; 9) Differentially spliced exons in ctrl siRNA vs. SYNCRIP siRNA; 10) Differentially expressed genes in ctrl siRNA vs. ILF2 siRNA; 11) Differntially spliced genes in ctrl siRNA vs. ILF2 siRNA; 12) Differentially spliced exons in ctrl siRNA vs. ILF2 siRNA

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Identification of SMCHD1 as a Novel Regulator of Alternative Splicing in FSHD2

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