Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
Nat Commun. 2023 Oct 12;14(1):6420. doi: 10.1038/s41467-023-42094-9.
Identification of factors that regulate chromatin condensation is important for understanding of gene regulation. High-mobility group AT-hook (HMGA) proteins 1 and 2 are abundant nonhistone chromatin proteins that play a role in many biological processes including tissue stem-progenitor cell regulation, but the nature of their protein function remains unclear. Here we show that HMGA2 mediates direct condensation of polynucleosomes and forms droplets with nucleosomes. Consistently, most endogenous HMGA2 localized to transposase 5- and DNase I-inaccessible chromatin regions, and its binding was mostly associated with gene repression, in mouse embryonic neocortical cells. The AT-hook 1 domain was necessary for chromatin condensation by HMGA2 in vitro and in cellulo, and an HMGA2 mutant lacking this domain was defective in the ability to maintain neuronal progenitors in vivo. Intrinsically disordered regions of other proteins could substitute for the AT-hook 1 domain in promoting this biological function of HMGA2. Taken together, HMGA2 may regulate neural cell fate by its chromatin condensation activity.
鉴定调控染色质凝聚的因素对于理解基因调控非常重要。高迁移率族 AT 钩（HMGA）蛋白 1 和 2 是丰富的非组蛋白染色质蛋白，在包括组织干细胞-祖细胞调节在内的许多生物学过程中发挥作用，但它们的蛋白质功能的性质仍不清楚。在这里，我们表明 HMGA2 介导多核小体的直接凝聚，并与核小体形成液滴。一致地，大多数内源性 HMGA2 定位于转座酶 5-和 DNase I 不可及的染色质区域，并且其结合主要与基因抑制相关，在小鼠胚胎新皮层细胞中。AT 钩 1 结构域是 HMGA2 在体外和细胞内进行染色质凝聚所必需的，并且缺乏该结构域的 HMGA2 突变体在体内维持神经元祖细胞的能力有缺陷。其他蛋白质的无规则结构域可以替代 AT 钩 1 结构域来促进 HMGA2 的这种生物学功能。总之，HMGA2 可能通过其染色质凝聚活性来调节神经细胞命运。
