小柯机器人

意大利特伦托大学Alessio Zippo、Alessandra Fasciani小组的一项最新研究表明，在Kabuki综合征患者中MLL4相关凝聚物平衡了多梳复合物介导的核机械应力。该研究于2020年11月9日发表于国际学术期刊《自然-遗传学》。

通过探究Kabuki综合征中KMT2D（也称为MLL4）单倍体剂量不足的影响，研究人员发现混合谱系白血病4（MLL4）通过液-液相分离促进了转录凝聚物的组装。MLL4功能丧失会损害多梳依赖性染色质区室化并改变核结构。通过抑制机械传感器ATR释放核机械应力，研究人员在体外和体内重新建立了间充质干细胞的机械信号传导及其对软骨细胞的调控。

这项研究佐证了以下观点：在Kabuki综合征中，MLL4单倍体剂量不足会导致染色质功能分区改变，从而决定了核的结构和机械性能。

据了解，调节基因表达所需的遗传元件包裹在活性和抑制性核凝聚物中。染色质区室包括转录簇，其动态建立和功能取决于转录因子、辅因子和基础转录机制之间发生的多价相互作用。然而，人们对染色质蛋白如何促进转录凝聚物的组装了解甚少。

附：英文原文

Title: MLL4-associated condensates counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki syndrome

Author: Alessandra Fasciani, Sarah DAnnunzio, Vittoria Poli, Luca Fagnocchi, Sven Beyes, Daniela Michelatti, Francesco Corazza, Laura Antonelli, Francesco Gregoretti, Gennaro Oliva, Romina Belli, Daniele Peroni, Enrico Domenici, Samuel Zambrano, Daniela Intartaglia, Carmine Settembre, Ivan Conte, Claudia Testi, Panagiotis Vergyris, Giancarlo Ruocco, Alessio Zippo

Issue&Volume: 2020-11-09

Abstract: The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depend on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However, how chromatin players contribute to the assembly of transcriptional condensates is poorly understood. By interrogating the effect of KMT2D (also known as MLL4) haploinsufficiency in Kabuki syndrome, we found that mixed lineage leukemia 4 (MLL4) contributes to the assembly of transcriptional condensates through liquid–liquid phase separation. MLL4 loss of function impaired Polycomb-dependent chromatin compartmentalization, altering the nuclear architecture. By releasing the nuclear mechanical stress through inhibition of the mechanosensor ATR, we re-established the mechanosignaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that, in Kabuki syndrome, the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.

DOI: 10.1038/s41588-020-00724-8

Source: https://www.nature.com/articles/s41588-020-00724-8

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex