小柯机器人

人类重复扩增疾病中转录凝聚物的功能，这一成果由德国马克斯·普朗克分子遗传学研究所Denes Hnisz小组经过不懈努力而取得。相关论文于2020年5月7日在线发表在《细胞》杂志上。

研究人员发现导致人类遗传性多指症的转录因子（TF）HOXD13，其丙氨酸重复扩增会改变其相分离能力以及与转录共激活因子共凝聚的能力。HOXD13重复扩增在体外和体内扰乱了含HOXD13凝聚物的组成，并在小鼠多指模型中以细胞特异性方式改变了转录程序。类似地，研究人员发现其他TF（HOXA13、RUNX2和TBP）中与疾病相关的重复扩增会改变其相分离。这些结果表明，转录凝聚物的非融合可能是导致人类疾病的基础。该研究提出了TF内在无序区域（IDR）的分子分类，它为解剖与转录失调相关疾病中TF的功能提供了参考。

据悉，在20多种人类遗传性疾病中存在氨基酸重复序列的扩增，并且许多发生在TF IDR中。这类疾病与蛋白质聚集有关，但聚集体对病理的贡献一直存在争议。

附：英文原文

Title: Unblending of Transcriptional Condensates in Human Repeat Expansion Disease

Author: Shaon Basu, Sebastian D. Mackowiak, Henri Niskanen, Dora Knezevic, Vahid Asimi, Stefanie Grosswendt, Hylkje Geertsema, Salaheddine Ali, Ivana Jerkovi, Helge Ewers, Stefan Mundlos, Alexander Meissner, Daniel M. Ibrahim, Denes Hnisz

Issue&Volume: 2020-05-07

Abstract: Expansions of amino acid repeats occur in >20 inherited human disorders, and manyoccur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Suchdiseases are associated with protein aggregation, but the contribution of aggregatesto pathology has been controversial. Here, we report that alanine repeat expansionsin the HOXD13 TF, which cause hereditary synpolydactyly in humans, alter its phaseseparation capacity and its capacity to co-condense with transcriptional co-activators.HOXD13 repeat expansions perturb the composition of HOXD13-containing condensatesin vitro and in vivo and alter the transcriptional program in a cell-specific manner in a mouse modelof synpolydactyly. Disease-associated repeat expansions in other TFs (HOXA13, RUNX2,and TBP) were similarly found to alter their phase separation. These results suggestthat unblending of transcriptional condensates may underlie human pathologies. Wepresent a molecular classification of TF IDRs, which provides a framework to dissectTF function in diseases associated with transcriptional dysregulation.

DOI: 10.1016/j.cell.2020.04.018

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30481-5