XIST restraint by AFF3 enables human neural and musculoskeletal development
Year: 2026
Type: preprint
Abstract: The underlying developmental mechanisms of defects in human organogenesis remain poorly defined. Pathogenic variants in AFF3, the super elongation complex subunit, cause a congenital disorder of neural and limb development, yet their developmental basis is unclear. Stem cell-based embryo model gastruloids show that AFF3, enriched in neural progenitors and neuromesodermal progenitors, is required for female neural and musculoskeletal development. AFF3 loss depletes neural and musculoskeletal lineages. Mechanistically, AFF3 restrains premature and excessive activation of the X-inactivation mediator XIST. Abnormal XIST upregulation represses autosomal genes required for neural and musculoskeletal development. Genetic deletion or pharmacological attenuation of XIST restores gastruloid morphogenesis, rescues neural and musculoskeletal development via autosomal genes, and improves cerebral organoid formation and neurogenesis after transplantation. These findings identify AFF3-mediated XIST restraint as an essential safeguard for early human organogenesis, and its failure can be traced back to gastrulation.
Source: Research Square
Authors: Ryohichi Sugimura, Yang Xiang, Guanchen Wu, Hongji Li, Alex To, Qiyan Wang, Amanda NM Looi, Yan Xue, Chloe Kan, Yiming Chao, Xu Jiang, Ke Fang, Xiaohong Cen, Yiyi Xuan, Degong Ruan, Chao Liang, Ziqi Huang, Siyuan Chen, Feiming Li, Yamei Jiang, Sang Jin Lee, Pentao Liu, Jin Liu, Zhuojuan Luo, Chengqi Lin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225391391