ARID1A 保障破骨细胞发生过程中细胞命运决定的定型分化。

ARID1A safeguards the canalization of the cell fate decision during osteoclastogenesis.

机构信息

Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.

出版信息

Nat Commun. 2024 Jul 17;15(1):5994. doi: 10.1038/s41467-024-50225-z.

DOI:10.1038/s41467-024-50225-z

PMID:39013863

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11252270/

Abstract

Chromatin remodeler ARID1A regulates gene transcription by modulating nucleosome positioning and chromatin accessibility. While ARID1A-mediated stage and lineage-restricted gene regulation during cell fate canalization remains unresolved. Using osteoclastogenesis as a model, we show that ARID1A transcriptionally safeguards the osteoclast (OC) fate canalization during proliferation-differentiation switching at single-cell resolution. Notably, ARID1A is indispensable for the transcriptional apparatus condensates formation with coactivator BRD4/lineage-specifying transcription factor (TF) PU.1 at Nfatc1 super-enhancer during safeguarding the OC fate canalization. Besides, the antagonist function between ARID1A-cBAF and BRD9-ncBAF complex during osteoclastogenesis has been validated with in vitro assay and compound mutant mouse model. Furthermore, the antagonistic function of ARID1A-"accelerator" and BRD9-"brake" both depend on coactivator BRD4-"clutch" during osteoclastogenesis. Overall, these results uncover sophisticated cooperation between chromatin remodeler ARID1A, coactivator, and lineage-specifying TF at super-enhancer of lineage master TF in a condensate manner, and antagonist between distinct BAF complexes in the proper and balanced cell fate canalization.

摘要

染色质重塑因子 ARID1A 通过调节核小体定位和染色质可及性来调节基因转录。然而，ARID1A 在细胞命运分化过程中对阶段和谱系限制的基因调控仍未得到解决。我们使用破骨细胞分化作为模型，表明 ARID1A 在单个细胞分辨率下的增殖-分化转换过程中，通过转录方式保护破骨细胞（OC）命运分化。值得注意的是，ARID1A 对于转录装置凝聚体的形成是必不可少的，在保护 OC 命运分化过程中，与共激活因子 BRD4/谱系特异性转录因子（TF）PU.1 一起形成 Nfatc1 超级增强子。此外，我们通过体外测定和化合物突变小鼠模型验证了 ARID1A-cBAF 和 BRD9-ncBAF 复合物在破骨细胞分化过程中的拮抗作用。此外，ARID1A-“加速器”和 BRD9-“刹车”的拮抗作用都依赖于破骨细胞分化过程中的共激活因子 BRD4-“离合器”。总的来说，这些结果揭示了染色质重塑因子 ARID1A、共激活因子和谱系特异性 TF 在凝聚体方式下在谱系主 TF 的超级增强子上的复杂合作，以及在适当和平衡的细胞命运分化中不同 BAF 复合物之间的拮抗作用。