The Genetic and Epigenetic Basis for FSHD

项目1 FSIHD的遗传学和表观遗传学基础 我们已经证明FSHD是由收缩-cfepencfenf或收缩非依赖性引起的 (FSHD2)D4Z4染色质结构的变化仅当这种收缩发生在 特定遗传背景(4qA161)。这导致假设D4Z4染色质的变化 4qA161单倍型上的结构是FSHD的重要病理基础。因此，长期目标是 确定特定的DNA序列和共同赋予致病性的表观遗传修饰 4qA161。目标1将鉴定疾病单倍型特有的序列变异并对其进行功能表征 远端重复单位和侧翼PLAM序列。最近的研究确定了FSHD基因的这一部分 作为最小的基本区域；目标2将识别和功能表征染色质结构 这个最小的必要区域测试了D4Z4重复调控DUX4表达并具有 在早期胚胎发育中的生物学作用；目标3将决定遗传和表观遗传学 D4Z4在人ES细胞中的特性以确定D4Z4在胚胎发育中的作用 FSHD的临床特点。

PROJECT 1 The Genetic and Epigenetic Basis for FSIHD We have demonstrated that FSHD is caused by a contraction-cfepencfenf (FSHD1) or contractionindependent (FSHD2) change in chromatin structure of D4Z4 only when this contraction occurs on a specific genetic background (4qA161). This leads to the hypothesis that a change in D4Z4 chromatin structure on the 4qA161 haplotype is essential for FSHD pathology. Therefore, the long-term goal is to identify the specific DNA sequences and the epigenetic modifications that together confer pathogenicity to 4qA161. Aim 1 will identify and functionally characterize the disease haplotype-specific sequence variants of the distal repeat unit and flanking pLAM sequence. Recent studies identified this part of the FSHD locus as the minimal essential region; Aim 2 will identify and functionally characterize the chromatin structure of this minimal essential region test the hypothesis that the D4Z4 repeats regulate DUX4 expression and have a biological role in early embryonic development; and Aim 3 will determine the genetic and epigenetic characteristics of D4Z4 in human ES cells to establish the developmental role of D4Z4 in relation to the clinical features of FSHD.