SMCHD1 Pathways as Candidate Targets for FSHD

SMCHD1 通路作为 FSHD 的候选目标

• 批准号: 10674006
• 负责人: Stephen J Tapscott
• 金额: $ 43.02万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674006
• 关键词: Affect; Binding; Binding Sites; Cell Differentiation process; Cell Reprogramming; Cells; Chromatin; Chromatin Structure; Complex; D4Z4; DNMT3B gene; Dependence; Development; Disease; Epigenetic Process; Facioscapulohumeral; Facioscapulohumeral Muscular Dystrophy; Failure; Family; Future; Gene Mutation; Genome; Goals; Health; Human; Intervention; Maintenance; Mediating; Modeling; Modification; Molecular; Molecular Biology; Muscle Cells; Mutation; Pathway interactions; Persons; Post-Translational Protein Processing; Production; Proteins; Regulation; Repetitive Sequence; Repression; Research; Role; Set protein; Skeletal Muscle; Testing; Validation; autosome; chromatin modification; epigenetic regulation; induced pluripotent stem cell; prevent; protein complex; recruit; stem cells; therapeutic development; therapy design; therapy development

PROJECT SUMMARY Facioscapulohumeral dystrophy (FSHD) affects ~1/10,000 people and is caused by decreased epigenetic repression of the DUX4 retrogene with subsequent mis-expression of DUX4 in skeletal muscle. As increasing the SMCHD1-mediated epigenetic repression at the D4Z4 locus silences DUX4 in FSHD1 and FSHD2 muscle cells, this application will take a direct molecular biology approach to identify the diversity of SMCHD1 complexes and the role of each component in establishing and maintaining repressive chromatin structure at the D4Z4 and preventing DUX4 expression in skeletal muscle. The broad and long-term goal is to determine the functional components of the SMCHD1 complexes at the D4Z4 locus as a basis for future therapies directed at increasing epigenetic repression. The major hypothesis is that SMCHD1 forms different interactions depending on post- translational modification, chromatin association, and developmental state of the cell, and that understanding the functional roles of the different complexes will provide simple reductionist models for testing candidate interventions. Aim 1 will determine the proteins complexed with SMCHD1 at the D4Z4 locus and their functional significance, chromatin association, and SUMO dependence. Aim 2 will determine the composition of SMCHD1 complexes at autosomal single copy loci in the genome compared to repetitive regions and to subdomains of the D4Z4. Aim 3 will identify the relative roles of SMCHD1 complex components in the establishment and maintenance of epigenetic modifications during stem cell reprogramming and differentiation. Together, these aims will add clarity to the components of SMCHD1 complexes and their functional roles in D4Z4 epigenetic repression, and provide new opportunities to design interventions to suppress DUX4 expression as a treatment for FSHD.

项目总结

项目成果

The prospects of targeting DUX4 in facioscapulohumeral muscular dystrophy.

• DOI: 10.1097/wco.0000000000000849
• 发表时间: 2020-10
• 期刊: Current opinion in neurology
• 影响因子: 4.8
• 作者: Bouwman LF;van der Maarel SM;de Greef JC
• 通讯作者: de Greef JC

A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.

• DOI: 10.1038/s41598-021-03030-3
• 发表时间: 2021-12-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Goossens R;Tihaya MS;van den Heuvel A;Tabot-Ndip K;Willemsen IM;Tapscott SJ;González-Prieto R;Chang JG;Vertegaal ACO;Balog J;van der Maarel SM
• 通讯作者: van der Maarel SM

Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures.

FSHD2 肌肉细胞中的小非编码 RNA 揭示了 DUX4 和 SMCHD1 特异性特征。

• DOI: 10.1093/hmg/ddy173
• 发表时间: 2018
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Lim,Jong-Won;Wong,Chao-Jen;Yao,Zizhen;Tawil,Rabi;vanderMaarel,SilvèreM;Miller,DanielG;Tapscott,StephenJ;Filippova,GalinaN
• 通讯作者: Filippova,GalinaN

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

• DOI: 10.1038/s41467-023-40992-6
• 发表时间: 2023-09-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Tapia del Fierro, Andres;den Hamer, Bianca;Benetti, Natalia;Jansz, Natasha;Chen, Kelan;Beck, Tamara;Vanyai, Hannah;Gurzau, Alexandra D.;Daxinger, Lucia;Xue, Shifeng;Ly, Thanh Thao Nguyen;Wanigasuriya, Iromi;Iminitoff, Megan;Breslin, Kelsey;Oey, Harald;Krom, Yvonne D.;van der Hoorn, Dinja;Bouwman, Linde F.;Johanson, Timothy M.;Ritchie, Matthew E.;Gouil, Quentin A.;Reversade, Bruno;Prin, Fabrice;Mohun, Timothy;van der Maarel, Silvere M.;Mcglinn, Edwina;Murphy, James M.;Keniry, Andrew;de Greef, Jessica C.;Blewitt, Marnie E.
• 通讯作者: Blewitt, Marnie E.

Dnmt3b regulates DUX4 expression in a tissue-dependent manner in transgenic D4Z4 mice.

• DOI: 10.1186/s13395-020-00247-0
• 发表时间: 2020-10-01
• 期刊: Skeletal muscle
• 影响因子: 4.9
• 作者: Bouwman LF;den Hamer B;Verveer EP;Lerink LJS;Krom YD;van der Maarel SM;de Greef JC
• 通讯作者: de Greef JC