Project 1: Pathways and mechanisms repressing D4Z4 repeats

项目 1：抑制 D4Z4 重复序列的途径和机制

• 批准号: 9767871
• 负责人: SILVERE M VAN DER MAAREL
• 金额: $ 21.08万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767871
• 关键词: Affect; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Clinical; D4Z4; DNMT3B gene; Development; Disease; Enhancers; Epigenetic Process; Facioscapulohumeral Muscular Dystrophy; Family; Genes; Genetic; Genetic Transcription; Genetic Variation; Goals; Human; Knowledge; Lead; Mediating; Mus; Muscle; Mutant Strains Mice; Mutate; Mutation; Myoblasts; Other Genetics; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Physical condensation; Relaxation; Repression; Skeletal Muscle; Somatic Cell; Syndrome; Testing; Transgenic Organisms; Translations; Variant; clinical phenotype; derepression; exome sequencing; genetic approach; genetic variant; genome-wide; insight; new therapeutic target; novel; novel therapeutics; segregation; therapy development

PROJECT 1: Pathways and mechanisms repressing D4Z4 repeats Abstract FSHD is caused by derepression of the DUX4 retrogene in skeletal muscle, either by contraction induced chromatin relaxation of the D4Z4 repeat array (FSHD1), or by mutations in the chromatin modifier SMCHD1 or yet unidentified chromatin modifiers (FSHD2). These facts lead to the major hypothesis that FSHD is caused by incomplete repeat-mediated epigenetic silencing of DUX4 in somatic cells and that targeting the D4Z4 chromatin structure is a rational therapy for FSHD. Therefore, the broad and long term goal is to identify the components and mechanisms of repeat-mediated epigenetic silencing at D4Z4 and to determine whether they function in convergent pathways that can be used to develop therapies that enhance epigenetic repression of D4Z4. The specific goal is to identify modulators of D4Z4 chromatin structure and DUX4 expression by a genetics approach. This will be accomplished by: Aim 1 identify additional DNMT3B mutations that cause FSHD2 and test the hypothesis that DNMT3B mutations with distinct clinical phenotypes have distinct epigenetic consequences at the D4Z4 repeat; Aim 2 identify novel genetic variants in chromatin modifiers that affect the D4Z4 chromatin structure in somatic cells and cause FSHD or act as a disease modifier; and Aim 3, establish the genome wide epigenetic and transcriptional consequences of mutations in FSHD2 genes and to identify enhancers repeat-mediated epigenetic silencing at D4Z4 as novel targets for therapy. Together, these aims will identify additional modifiers of D4Z4 repression and their epigenetic activity, and establish which modifiers of D4Z4 chromatin structure can be targeted for FSHD therapy. The significance of these studies is that identifying the components and mechanisms of repeat-mediated epigenetic silencing of DUX4 will facilitate the development of new drug therapies in FSHD

项目1：抑制D4Z4重复的途径和机制 摘要 FSHD是由骨骼肌中DUX4逆转录基因的去抑制引起的， D4Z4重复序列阵列（FSHD1）的染色质松弛，或染色质修饰剂SMCHD1或 尚未鉴定的染色质修饰剂（FSHD 2）。这些事实导致了一个主要假设，即FSHD是由 通过体细胞中DUX4的不完全重复介导的表观遗传沉默和靶向D4Z4的表观遗传沉默， 染色质结构是FSHD的合理治疗方法。因此，广泛和长期的目标是确定 重复介导的表观遗传沉默在D4Z4的组成部分和机制，并确定它们是否 在会聚途径中起作用，可用于开发增强表观遗传抑制的疗法， D4Z4具体的目标是通过免疫组化鉴定D4Z4染色质结构和DUX4表达的调节剂。 遗传学方法。这将通过以下方式实现：目的1鉴定引起以下疾病的其他DNMT3B突变： FSHD 2，并检验具有不同临床表型的DNMT 3B突变具有不同临床表型的假设。 D4Z4重复序列的表观遗传后果;目的2鉴定染色质修饰剂中的新遗传变体， 影响体细胞中的D4Z4染色质结构并引起FSHD或作为疾病调节剂;以及目的3， 建立FSHD 2基因突变的全基因组表观遗传和转录后果， 鉴定增强子重复介导的D4Z4表观遗传沉默作为新的治疗靶点。所有这些 目的是确定D4Z4抑制的其他修饰剂及其表观遗传活性，并确定 D4Z4染色质结构的修饰剂可以作为FSHD治疗的靶点。这些研究的意义在于 确定DUX4重复介导的表观遗传沉默的组分和机制将有助于 FSHD新药物治疗的开发