ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling

Mingyi Zhang, Tingwei Guo, Fei Pei, Jifan Feng, Junjun Jing, Jian Xu, Takahiko Yamada, Thach-Vu Ho, Jiahui Du, Prerna Sehgal and Yang Chai ()
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Mingyi Zhang: University of Southern California
Tingwei Guo: University of Southern California
Fei Pei: University of Southern California
Jifan Feng: University of Southern California
Junjun Jing: University of Southern California
Jian Xu: University of Southern California
Takahiko Yamada: University of Southern California
Thach-Vu Ho: University of Southern California
Jiahui Du: University of Southern California
Prerna Sehgal: University of Southern California
Yang Chai: University of Southern California

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs’ quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.

Date: 2024
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DOI: 10.1038/s41467-024-48285-2

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