Canonical BAF complex orchestrates mesenchymal stem cell niche composition and fate via cofactor-guided chromatin remodeling [scATAC-seq]

The canonical BAF (BRG1/BRM-associated factor) chromatin remodeling complex plays a pivotal role in governing stem cell behavior, yet how it regulates adult stem cell niche remains unclear. Here, we show that ARID1-containing cBAF complex orchestrates the spatial organization of the mesenchymal stem cell niche and fate in the adult mouse incisor. Dual loss of ARID1A and ARID1B in Gli1+ mesenchymal stem cells using conditional knockout mouse models disturbs chromatin accessibility in a cell-type-specific manner and alters cofactor recruitment, leading to niche cell disorganization, disrupting progenitor cells (transit-amplifying cells, TACs) fate commitment during tissue homeostasis. Single-cell multi-omics profiling and in vivo functional validations reveal that the cBAF complex partners with DLX2 to coordinate niche cell composition and recruits FOXO1 and DLX2 to balance TAC proliferation and differentiation. Our findings establish cBAF as a master regulator of chromatin state and microenvironment architecture, essential for maintaining adult mesenchymal stem cell function and tissue homeostasis. Overall design: Single-cell transposase-accessible chromatin were obtained from the digested proximal region of mouse incisor of at 4 days post-tamoxifen induction for DKO mice at the age of 1 month.

经典BAF（BRG1/BRM-associated factor）染色质重塑复合物在调控干细胞行为中发挥关键作用，但其调控成体干细胞巢的具体机制仍不明晰。本研究证实，含ARID1的cBAF复合物可调控成年小鼠切牙间质干细胞巢的空间架构与细胞命运。通过条件性基因敲除小鼠模型，在Gli1阳性间质干细胞中同时敲除ARID1A与ARID1B后，会以细胞类型特异性方式扰乱染色质开放状态并改变辅因子招募，进而引发干细胞巢细胞结构紊乱，破坏组织稳态过程中祖细胞（转运扩增细胞，transit-amplifying cells, TACs）的命运决定。单细胞多组学分析与体内功能验证实验表明，cBAF复合物可与DLX2协同调控干细胞巢细胞组成，并招募FOXO1与DLX2以平衡转运扩增细胞的增殖与分化。本研究结果确立了cBAF复合物作为染色质状态与微环境结构核心调控因子的地位，其对维持成体间质干细胞功能与组织稳态至关重要。整体实验设计：对1月龄的双敲除（DKO）小鼠，在他莫昔芬诱导4天后，从小鼠切牙消化后的近端区域获取单细胞转座酶可及染色质样本。