Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
Cell Rep. 2020 Nov 17;33(7):108395. doi: 10.1016/j.celrep.2020.108395.
The mammalian SWitch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling BAF (BRG1/BRM-associated factor) complex plays an essential role in developmental and pathological processes. We show that the deletion of Baf155, which encodes a subunit of the BAF complex, in the Tie2(+) lineage (Baf155 (CKO) leads to defects in yolk sac myeloid and definitive erythroid (EryD) lineage differentiation from erythromyeloid progenitors (EMPs). The chromatin of myeloid gene loci in Baf155 CKO EMPs is mostly inaccessible and enriched mainly by the ETS binding motif. BAF155 interacts with PU.1 and is recruited to PU.1 target gene loci together with p300 and KDM6a. Treatment of Baf155 CKO embryos with GSK126, an H3K27me2/3 methyltransferase EZH2 inhibitor, rescues myeloid lineage gene expression. This study uncovers indispensable BAF-mediated chromatin remodeling of myeloid gene loci at the EMP stage. Future studies exploiting epigenetics in the generation and application of EMP derivatives for tissue repair, regeneration, and disease are warranted.
哺乳动物的 SWI/SNF 染色质重塑 BAF（BRG1/BRM 相关因子）复合物在发育和病理过程中发挥着重要作用。我们发现，BAF 复合物的一个亚基 Baf155 的缺失（Baf155（CKO））会导致从红系髓系祖细胞（EMPs）分化而来的卵黄囊髓系和确定性红细胞（EryD）谱系分化缺陷。Baf155 CKO EMPs 中的髓系基因座的染色质大多不可接近，并且主要富集 ETS 结合基序。BAF155 与 PU.1 相互作用，并与 p300 和 KDM6a 一起被募集到 PU.1 靶基因座。用 H3K27me2/3 甲基转移酶 EZH2 抑制剂 GSK126 处理 Baf155 CKO 胚胎，可挽救髓系基因表达。这项研究揭示了 EMP 阶段髓系基因座必不可少的 BAF 介导的染色质重塑。未来的研究需要利用表观遗传学来生成和应用 EMP 衍生物，以用于组织修复、再生和疾病治疗。
