Unblending of Transcriptional Condensates in Human Repeat Expansion Disease
Unblending of Transcriptional Condensates in Human Repeat Expansion Disease
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DOI：
10.1016/j.cell.2020.04.018
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发表时间：
2020-05-28
期刊：
影响因子：
64.5
通讯作者：
Hnisz, Denes
中科院分区：
文献类型：
--
作者：
Basu, Shaon;Mackowiak, Sebastian D.;Hnisz, Denes
氨基酸重复序列的扩展发生在>；20遗传性人类疾病中，许多发生在转录因子(TF)的固有无序区域(IDR)。这类疾病与蛋白质聚集有关，但聚集在病理中的作用一直存在争议。在这里，我们报告了Hoxd13 Tf中的丙氨酸重复扩张，这导致了人类遗传性并多指，改变了它的相分离能力和它与转录共激活子共缩合的能力。Hoxd13重复扩张在体外和体内扰乱了含有Hoxd13的冷凝物的组成，并以细胞特有的方式改变了并指鼠模型的转录程序。在其他TF(HOXA13、RUNX2和TBP)中与疾病相关的重复序列的扩张也同样改变了它们的时相分离。这些结果表明，转录缩合物的解混可能是人类病理的基础。我们提出了转铁蛋白IDRs的分子分类，这提供了一个框架，以剖析与转录失调相关疾病的转铁蛋白功能。
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.