XIST restraint by AFF3 enables human neural and musculoskeletal development

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.

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Publication Details

Journal
Research Square
Published
2026-11-06
DOI
https://doi.org/10.21203/rs.3.rs-11233698/v1
Primary Topic
Developmental Biology and Gene Regulation
Type
preprint
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preprint

XIST restraint by AFF3 enables human neural and musculoskeletal development

Pentao Liu, Chengqi Lin, Degong Ruan, Yiming Chao et al.
Research Square
Developmental Biology and Gene Regulation
preprint

XIST restraint by AFF3 enables human neural and musculoskeletal development

Pentao Liu, Chengqi Lin, Degong Ruan, Yiming Chao, Jin Liu, Qiyan Wang, Zhuojuan Luo, Ke Fang, Ryohichi Sugimura, Yiyi Xuan, Alex To, Sang Jin Lee, Yan Xue, Yang Xiang, Chao Liang, Chloe Kan, Yamei Jiang, Hongji 、LI, Guanchen Wu, Ziqi Huang, Siyuan Chen, Xiaohong Cen, Xu Jiang, Amanda NM Looi, Feiming Li
preprint en

Abstract

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.

Research Square
Chinese University of Hong Kong, Shenzhen (CN), Southeast University (CN), University of Hong Kong (HK)
Good health and well-being
Developmental Biology and Gene Regulation
DOIOpen Access PDFOpenAlex
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