Sorek Matan, Cohen Lea R Z, Meshorer Eran
Edmond and Lily Safra Center for Brain Sciences, Edmond J. Safra Campus, Jerusalem, Hebrew University of Jerusalem, 9190401, Israel.
Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, Jerusalem, Hebrew University of Jerusalem, 9190401, Israel.
NAR Genom Bioinform. 2019 Jul 30;1(1):e3. doi: 10.1093/nargab/lqz003. eCollection 2019 Apr.
The human genome contains dozens of genes that encode for proteins containing long poly-glutamine repeats (polyQ, usually encoded by CAG codons) of 10Qs or more. However, only nine of these genes have been reported to expand beyond the healthy variation and cause diseases. To address whether these nine disease-associated genes are unique in any way, we compared genetic and epigenetic features relative to other types of genes, especially repeat containing genes that do not cause diseases. Our analyses show that in pluripotent cells, the nine polyQ disease-related genes are characterized by an open chromatin profile, enriched for active chromatin marks and depleted for suppressive chromatin marks. By contrast, genes that encode for polyQ-containing proteins that are not associated with diseases, and other repeat containing genes, possess a suppressive chromatin environment. We propose that the active epigenetic landscape support decreased genomic stability and higher susceptibility for expansion mutations.
人类基因组包含数十个基因，这些基因编码含有10个或更多谷氨酰胺长重复序列（polyQ，通常由CAG密码子编码）的蛋白质。然而，据报道，这些基因中只有9个会超出健康变异范围并导致疾病。为了探究这9个与疾病相关的基因是否在任何方面具有独特性，我们比较了它们相对于其他类型基因的遗传和表观遗传特征，特别是那些含有不致病重复序列的基因。我们的分析表明，在多能细胞中，这9个与多聚谷氨酰胺疾病相关的基因具有开放的染色质图谱，富含活性染色质标记，而抑制性染色质标记则较少。相比之下，编码与疾病无关的含多聚谷氨酰胺蛋白质的基因，以及其他含有重复序列的基因，则具有抑制性染色质环境。我们认为，活跃的表观遗传格局会降低基因组稳定性，并增加发生扩增突变的易感性。
