Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
Blood Adv. 2023 Nov 14;7(21):6553-6566. doi: 10.1182/bloodadvances.2023009946.
The adenosine triphosphate (ATP)-dependent chromatin remodeling complex, SWItch/Sucrose Non-Fermentable (SWI/SNF), has been implicated in normal hematopoiesis. The AT-rich interaction domain 1B (ARID1B) and its paralog, ARID1A, are mutually exclusive, DNA-interacting subunits of the BRG1/BRM-associated factor (BAF) subclass of SWI/SNF complex. Although the role of several SWI/SNF components in hematopoietic differentiation and stem cell maintenance has been reported, the function of ARID1B in hematopoietic development has not been defined. To this end, we generated a mouse model of Arid1b deficiency specifically in the hematopoietic compartment. Unlike the extensive phenotype observed in mice deficient in its paralog, ARID1A, Arid1b knockout (KO) mice exhibited a modest effect on steady-state hematopoiesis. Nonetheless, transplantation experiments showed that the reconstitution of myeloid cells in irradiated recipient mice was dependent on ARID1B. Furthermore, to assess the effect of the complete loss of ARID1 proteins in the BAF complex, we generated mice lacking both ARID1A and ARID1B in the hematopoietic compartment. The double-KO mice succumbed to acute bone marrow failure resulting from complete loss of BAF-mediated chromatin remodeling activity. Our Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed that >80% of loci regulated by ARID1B were distinct from those regulated by ARID1A; and ARID1B controlled expression of genes crucial in myelopoiesis. Overall, loss of ARID1B affected chromatin dynamics in murine hematopoietic stem and progenitor cells, albeit to a lesser extent than cells lacking ARID1A.
三磷酸腺苷（ATP）依赖性染色质重塑复合物 SWItch/Sucrose Non-Fermentable（SWI/SNF）已被牵涉到正常造血过程中。富含 A/T 的相互作用结构域 1B（ARID1B）及其同源物 ARID1A 是 BRG1/BRM 相关因子（BAF）亚类 SWI/SNF 复合物中相互排斥的 DNA 相互作用亚基。尽管已经报道了几个 SWI/SNF 成分在造血分化和干细胞维持中的作用，但 ARID1B 在造血发育中的功能尚未确定。为此，我们专门在造血细胞中生成了 Arid1b 缺失的小鼠模型。与缺乏其同源物 ARID1A 的小鼠中观察到的广泛表型不同，Arid1b 敲除（KO）小鼠对稳态造血的影响不大。尽管如此，移植实验表明，ARID1B 依赖于受照射受体小鼠中髓样细胞的重建。此外，为了评估 BAF 复合物中完整缺失 ARID1 蛋白的效果，我们在造血细胞中生成了缺乏 ARID1A 和 ARID1B 的小鼠。双 KO 小鼠因 BAF 介导的染色质重塑活性完全丧失而死于急性骨髓衰竭。我们的高通量转座酶可及染色质分析（ATAC-seq）分析表明，>80%受 ARID1B 调控的基因座与受 ARID1A 调控的基因座不同；并且 ARID1B 控制了在髓样细胞生成中至关重要的基因的表达。总体而言，与缺乏 ARID1A 的细胞相比，ARID1B 缺失对小鼠造血干细胞和祖细胞中的染色质动力学有一定影响。
