Ma Gang, Fu Xiuling, Zhou Lulu, Babarinde Isaac A, Shi Liyang, Yang Wenting, Chen Jiao, Xiao Zhen, Qiao Yu, Ma Lisha, Ou Yuhao, Li Yuhao, Chang Chen, Deng Boping, Zhang Ran, Sun Li, Tong Guoqing, Li Dongwei, Li Yiming, Hutchins Andrew P
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China.
Nat Cell Biol. 2025 Feb;27(2):232-245. doi: 10.1038/s41556-024-01595-5. Epub 2025 Jan 9.
The nuclear matrix, a proteinaceous gel composed of proteins and RNA, is an important nuclear structure that supports chromatin architecture, but its role in human pluripotent stem cells (hPSCs) has not been described. Here we show that by disrupting heterogeneous nuclear ribonucleoprotein U (HNRNPU) or the nuclear matrix protein, Matrin-3, primed hPSCs adopted features of the naive pluripotent state, including morphology and upregulation of naive-specific marker genes. We demonstrate that HNRNPU depletion leads to increased chromatin accessibility, reduced DNA contacts and increased nuclear size. Mechanistically, HNRNPU acts as a transcriptional co-factor that anchors promoters of primed-specific genes to the nuclear matrix with POLII to promote their expression and their RNA stability. Overall, HNRNPU promotes cell-type stability and when reduced promotes conversion to earlier embryonic states.
核基质是一种由蛋白质和RNA组成的蛋白质凝胶，是支持染色质结构的重要核结构，但其在人类多能干细胞（hPSCs）中的作用尚未见报道。在此，我们表明，通过破坏异质性核核糖核蛋白U（HNRNPU）或核基质蛋白Matrin-3，已分化的hPSCs呈现出原始多能状态的特征，包括形态以及原始特异性标记基因的上调。我们证明，HNRNPU的缺失导致染色质可及性增加、DNA接触减少以及核尺寸增大。从机制上讲，HNRNPU作为一种转录辅因子，通过POLII将已分化特异性基因的启动子锚定到核基质上，以促进其表达及其RNA稳定性。总体而言，HNRNPU促进细胞类型稳定性，当其减少时则促进向早期胚胎状态的转化。
