清华大学颉伟等研究人员合作揭示早期发育过程中失活X染色体结构的逐步从头建立。相关论文于2024年9月10日在线发表于国际学术期刊《自然—遗传学》。

研究人员在小鼠胚外谱系和胚外内胚层（XEN）细胞系中的失活X染色体上鉴定出一种Xist分隔的大域结构（X-megadomain），并在胚胎谱系中暂时观察到这一结构，在后期则以谱系特异性方式形成由Dxz4划定的megadomain。X-megadomain边界与早期胚胎中Xist激活所需的Xist调控区中的强增强子活性和黏连蛋白结合位置重合。

Xist调控区的破坏或黏连蛋白降解会削弱胚外内胚层细胞中的X-megadomain，并导致Xist附近调控元件和基因的异位激活，表明黏连蛋白在调控元件上的加载促进了X-megadomain的形成并限制了局部基因活性。这些数据揭示了在X染色体失活早期阶段，通过逐步的X染色体折叠和转录调控，实现了关键基因的激活和全局的基因沉默。

据介绍，X染色体失活触发了转录和染色体结构的显著重编程。然而，失活X染色体的染色质结构在体内如何从头建立仍然不清楚。

附：英文原文

Title: Stepwise de novo establishment of inactive X chromosome architecture in early development

Author: Du, Zhenhai, Hu, Liangjun, Zou, Zhuoning, Liu, Meishuo, Li, Zihan, Lu, Xukun, Harris, Clair, Xiang, Yunlong, Chen, Fengling, Yu, Guang, Xu, Kai, Kong, Feng, Xu, Qianhua, Huang, Bo, Liu, Ling, Fan, Qiang, Wang, Haifeng, Kalantry, Sundeep, Xie, Wei

Issue&Volume: 2024-09-10

Abstract: X chromosome inactivation triggers a dramatic reprogramming of transcription and chromosome architecture. However, how the chromatin organization of inactive X chromosome is established de novo in vivo remains elusive. Here, we identified an Xist-separated megadomain structure (X-megadomains) on the inactive X chromosome in mouse extraembryonic lineages and extraembryonic endoderm (XEN) cell lines, and transiently in the embryonic lineages, before Dxz4-delineated megadomain formation at later stages in a strain-specific manner. X-megadomain boundary coincides with strong enhancer activities and cohesin binding in an Xist regulatory region required for proper Xist activation in early embryos. Xist regulatory region disruption or cohesin degradation impaired X-megadomains in extraembryonic endoderm cells and caused ectopic activation of regulatory elements and genes near Xist, indicating that cohesin loading at regulatory elements promotes X-megadomains and confines local gene activities. These data reveal stepwise X chromosome folding and transcriptional regulation to achieve both essential gene activation and global silencing during the early stages of X chromosome inactivation.

DOI: 10.1038/s41588-024-01897-2

Source: https://www.nature.com/articles/s41588-024-01897-2