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.

调节基因表达所需的遗传元件被分配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，染色质参与者如何促进转录凝聚物的组装却知之甚少。通过询问KMT2D（也称为MLL4）在歌舞伎综合征中的单倍体不足，我们发现混合谱系白血病 4（MLL4）通过液 - 液相分离有助于转录凝聚物的组装。MLL4 功能丧失损害多梳依赖性染色质区室化，改变核结构。通过抑制机械传感器 ATR 释放核机械应力，我们重新建立了间充质干细胞的机械信号传导及其在体外和体内对软骨细胞的承诺。这项研究支持这样一种观点，即在歌舞伎综合征中，MLL4 的单倍体不足会导致染色质的功能分配发生改变，这决定了细胞核的结构和机械特性。