Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Institute for Chemistry and Biochemistry, Free University Berlin, 14195 Berlin, Germany.
Cell. 2020 May 28;181(5):1062-1079.e30. doi: 10.1016/j.cell.2020.04.018. Epub 2020 May 7.
Expansions of amino acid repeats occur in >20 inherited human disorders, and many occur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Such diseases are associated with protein aggregation, but the contribution of aggregates to pathology has been controversial. Here, we report that alanine repeat expansions in the HOXD13 TF, which cause hereditary synpolydactyly in humans, alter its phase separation capacity and its capacity to co-condense with transcriptional co-activators. HOXD13 repeat expansions perturb the composition of HOXD13-containing condensates in vitro and in vivo and alter the transcriptional program in a cell-specific manner in a mouse model of synpolydactyly. Disease-associated repeat expansions in other TFs (HOXA13, RUNX2, and TBP) were similarly found to alter their phase separation. These results suggest that unblending of transcriptional condensates may underlie human pathologies. We present a molecular classification of TF IDRs, which provides a framework to dissect TF function in diseases associated with transcriptional dysregulation.
氨基酸重复扩展发生在 >20 种遗传性人类疾病中，其中许多发生在转录因子 (TF) 的无规则区域 (IDR) 中。此类疾病与蛋白质聚集有关，但聚集物对病理学的贡献一直存在争议。在这里，我们报告了 HOXD13 TF 中的丙氨酸重复扩展，该扩展导致人类遗传性并指畸形，改变了其相分离能力及其与转录共激活因子共凝聚的能力。HOXD13 重复扩展扰乱了 HOXD13 包含的凝聚物的组成在体外和体内，并以一种细胞特异性的方式改变了在并指畸形的小鼠模型中的转录程序。在其他 TF（HOXA13、RUNX2 和 TBP）中发现的与疾病相关的重复扩展也同样改变了它们的相分离。这些结果表明，转录凝聚物的去混合可能是人类病理学的基础。我们提出了一个 TF IDR 的分子分类，为解析与转录失调相关的疾病中的 TF 功能提供了一个框架。
