Requisite chromatin remodeling for myeloid and erythroid lineage differentiation from erythromyeloid progenitors

The mammalian SWI/SNF chromatin-remodeling BAF (BRG1/BRM-associated factor) complex has an essential role in developmental and pathological processes. We show that deletion of Baf155 encoding 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 generation and application of EMP derivatives for tissue repair, regeneration, and disease are warranted.

哺乳动物SWI/SNF染色质重塑BAF（BRG1/BRM-associated factor）复合物在发育与病理过程中发挥关键调控作用。本研究发现，在Tie2阳性谱系中敲除BAF复合物亚基编码基因Baf155（Baf155 CKO），可导致卵黄囊髓系及定型红细胞系（definitive erythroid, EryD）从红髓系祖细胞（erythromyeloid progenitors, EMPs）的分化出现异常。Baf155 CKO红髓系祖细胞内，髓系基因位点的染色质可及性显著降低，且主要富集ETS结合基序。BAF155可与转录因子PU.1相互作用，并与p300、KDM6a共同被招募至PU.1靶基因位点。使用H3K27二/三甲基转移酶EZH2抑制剂GSK126处理Baf155 CKO胚胎，可挽救髓系谱系基因的表达水平。本研究揭示了红髓系祖细胞阶段，BAF介导的髓系基因位点染色质重塑具有不可或缺的关键作用。未来有必要开展相关研究，利用表观遗传学技术生成并应用红髓系祖细胞衍生物，用于组织修复、再生及疾病治疗。