面肩肱型肌营养不良
DNA甲基化
表观遗传学
基因沉默
生物
肌营养不良
背景(考古学)
遗传学
甲基化
DNA
基因
基因表达
古生物学
作者
Mitsuru Sasaki-Honda,Tatsuya Jonouchi,Meni Arai,Jingsha He,Kazusa Okita,Shigeki Sakurai,Takuya Yamamoto,Hiroyuki Sakurai
标识
DOI:10.1101/2022.04.12.487997
摘要
Facioscapulohumeral muscular dystrophy (FSHD), a progressive skeletal muscle disorder, is epigenetically characterized by DNA hypomethylation of the D4Z4 repeats in the 4q35 region, which enables aberrant DUX4 expression. Sustainable DUX4 suppression is thus a promising therapeutic strategy by which to prevent disease progression, but most of the supposed methods to achieve this depend on the expression of a mediator biochemical entity that would potentially narrow the quality of life of individuals with FSHD in the clinical context. In this study, we report that by applying hit-and-run silencing with dCas9-mediated epigenetic editing targeting DNA hypomethylation on D4Z4 repeats, we could achieve the suppression of endogenous DUX4 in our FSHD patient-derived iPSC model. Notably, DNA methylation was significantly upregulated in FSHD cells and suppression effects were observed for at least two weeks after intervention, which was not the case with transient treatments of typical dCas9-KRAB alone. Off-target analysis showed that despite the potential genome-wide risk for DNA methylation, the impact on the transcriptome was limited. We propose that hit-and-run silencing could be a promising option to prevent disease progression with minimum intervention for individuals with FSHD, motivating further study for clinical development.
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