SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

Fierro, Andrés Tapia del; B, den Hamer; Jansz, Natasha; Chen, K; Beck, Tamara; Vanyai, Hannah K.; Benetti, Natalia; Gurzau, Alexandra D.; Daxinger, Lucia; Xue, Sheng‐Li; Tt, Nguyen; Wanigasuriya, Iromi; Breslin, Kelsey; H, Oey; Krom, Yvonne D.; D, van der Hoorn; Lf, Bouwman; Ritchie, M. R.; Reversade, Bruno; F, Prin; Mohun, Tim; Maarel, Silvère M. van der; McGlinn, Edwina; Jm, Murphy; Keniry, Andrew; Jc, de Greef; Me, Blewitt

doi:10.1101/2021.05.12.443934

Cited by 5 publications

(8 citation statements)

References 88 publications

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“…Smchd1-GFP NSC ChIP-seq data was obtained from the GEO database, accession GSE111722 11 and GSE174066 33 . Smchd1 MEF ChIP-seq data was obtained from the GEO database, accession GSE111820 13 .…”

Section: Methodsmentioning

confidence: 99%

“…2D). We have repeated the analysis for another available NSC Smchd1-GFP ChIP-seq dataset 33 and found Smchd1 binds 1.38 more to mis-spliced exons compared to all expressed exons (p < 0.00001, Fisher's exact test) and specifically binds more to excluded exons (p < 0.009, student's t-test, Supp. Fig.…”

Section: Smchd1 Binding Is Enriched At Mis-spliced Exonsmentioning

confidence: 99%

“…3A). We repeated the analysis for Smchd1 binding sites identified in a different NSC dataset 33 or in MEFs 13 and also found a significant enrichment of RNAPII pSer2 at Smchd1-bound mis-spliced exons (Supp. Fig.…”

Section: Smchd1 Binding Correlates With Rnapii Stalling At Mis-splice...mentioning

confidence: 99%

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SMCHD1 loss triggers DUX4 expression by disrupting splicing in FSHD2

Engal

Sharma

Taqatqa

et al. 2023

Preprint

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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 can lead to DUX4 expression and FSHD pathogenesis. Analyzing RNA-seq data from muscle biopsies of FSHD2 patients and FSHD2 mouse model we found that hundreds of genes were mis-spliced upon SMCHD1 mutation. At least 20% of mis-spliced genes were associated with abnormalities of the musculature. Moreover, we show that mis-spliced exons tend to be bound by SMCHD1, and SMCHD1 bound exons demonstrate slower elongation rate, suggesting SMCHD1 binding promotes exon exclusion by slowing RNA polymerase II (RNAPII). Specifically, we discovered that SMCHD1 mutations promotes the splicing of the DNMT3B1 isoform of DNMT3B by perturbing RNAPII elongation rate and recruitment of the splicing factor RBM5. The mis-splicing of DNMT3B leads to hypomethylation of the D4Z4 region and to DUX4 overexpression. These results suggest that mis-splicing by SMCHD1 may play a major role in FSHD2 pathogenesis by promoting mis-splicing of different targets including DNMT3B, and highlight the potential for targeting splicing as a therapeutic strategy for this disorder.

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Section: Methodsmentioning

confidence: 99%

Section: Smchd1 Binding Is Enriched At Mis-spliced Exonsmentioning

confidence: 99%

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SMCHD1 loss triggers DUX4 expression by disrupting splicing in FSHD2

Engal

Sharma

Taqatqa

et al. 2023

Preprint

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show abstract

“…3A). We repeated the analysis for Smchd1 binding sites identified in a different NSC dataset 29 or MEFs 13 and also found a significant enrichment of RNAPII pSer2 at Smchd1bound mis-spliced exons (Supplementary Fig. S3A-B).…”

Section: Smchd1 Binding Correlates With Rnapii Stalling At Mis-splice...mentioning

confidence: 97%

“…2D). We repeated the analysis for another available NSC Smchd1-GFP ChIP-seq dataset 29 and found Smchd1 binds 1.38 more to mis-spliced exons compared to all expressed exons (p < 0.00001, Fisher's exact test) and specifically binds more to excluded exons (p < 0.009, student's t-test, Supplementary Fig. S2A-C).…”

Section: Smchd1 Binding Is Enriched At Mis-spliced Exonsmentioning

confidence: 99%

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

Salton,

Engal,

Sharma

et al. 2023

Preprint

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SMCHD1 is a non-canonical SMC protein and an epigenetic regulator. Mutations in SMCHD1 cause facioscapulohumeral muscular dystrophy type 2 (FSHD2), a genetic disorder characterized by progressive muscle weakness and wasting, believed to be caused by aberrant expression of DUX4 in muscle cells. Here we demonstrate a new role for SMCHD1 as a regulator of alternative splicing in various cell types. We show how SMCHD1 loss cause splicing alterations of DNMT3B which can lead to hypomethylation, DUX4 expression, and FSHD pathogenesis. Analyzing RNA-seq data from muscle biopsies of FSHD2 patients and Smchd1 knocked out cells, we found mis-splicing of hundreds of genes upon SMCHD1 loss. At least 20% of mis-spliced genes were associated with abnormalities of the musculature. Moreover, mis-spliced exons tend to be bound by SMCHD1, and bound exons demonstrate a slower elongation rate, suggesting SMCHD1 binding promotes exon exclusion by slowing RNAPII, and recruitment of the splicing factor RBM5. The mis-splicing of DNMT3B leads to hypomethylation of the D4Z4 region and to DUX4 overexpression. These results suggest that mis-splicing by SMCHD1 may play a major role in FSHD2 pathogenesis by promoting the mis-splicing of different targets including DNMT3B, and highlight the potential for targeting splicing as a therapeutic strategy.

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Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo

et al. 2022

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Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not deplete these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.

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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

Cited by 5 publications

References 88 publications

SMCHD1 loss triggers DUX4 expression by disrupting splicing in FSHD2

SMCHD1 loss triggers DUX4 expression by disrupting splicing in FSHD2

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

Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo

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