Project 1: Pathways and mechanisms repressing D4Z4 repeats

项目1：抑制D4Z4重复的途径和机制 摘要 FSHD是由骨骼肌中DUX4逆转录酶基因的去抑制引起的，或者是由收缩引起的 D4Z4重复序列(FSHD1)的染色质松弛，或染色质修饰物Smchd1或 尚未确定的染色质修饰物(FSHD2)。这些事实导致了FSHD是由 不完全重复序列介导的DUX4在体细胞中的表观遗传沉默及针对D4Z4的沉默 染色质结构是治疗FSHD的合理方法。因此，广泛和长期的目标是确定 重复序列介导的D4Z4表观遗传沉默的成分和机制以及它们是否 在汇聚通路中发挥作用，可用于开发增强表观遗传抑制的治疗方法 D4Z4。具体的目标是通过一种方法鉴定D4Z4染色质结构和DUX4表达的调节子 遗传学方法。这将通过以下方式实现：目标1确定导致 FSHD2和检验具有不同临床表型的Dnmt3b突变具有明显不同的假设 D4Z4重复的表观遗传后果；目标2识别染色质修饰物中的新遗传变异， 影响体细胞中的D4Z4染色质结构并导致FSHD或起到疾病修饰物的作用；以及目标3， 建立全基因组范围内FSHD2基因突变的表观遗传和转录后果 确定增强子重复序列介导的D4Z4表观遗传沉默是治疗的新靶点。加在一起，这些 AIMS将确定D4Z4抑制的其他修饰物及其表观遗传活性，并确定 D4Z4染色质结构的修饰物可作为FSHD治疗的靶点。这些研究的意义在于 识别重复序列介导的DUX4表观遗传沉默的成分和机制将有助于 FSHD的新药治疗进展

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