Abstract：
Chromatin priming promotes cell-type-specific gene expression, lineage differentiation, and development. The mechanism of chromatin priming has not been fully understood. Here, we report that mouse hematopoietic stem and progenitor cells (HSPCs) lacking the Baf155 subunit of the BAF (BRG1/BRM-associated factor) chromatin remodeling complex produce a significantly reduced number of mature blood cells, leading to a failure of hematopoietic regeneration upon transplantation and 5-fluorouracil (5-FU) injury. Baf155-deficient HSPCs generate particularly fewer neutrophils, B cells, and CD8+ T cells at homeostasis, supporting a more immune-suppressive tumor microenvironment and enhanced tumor growth. Single-nucleus multiomics analysis reveals that Baf155-deficient HSPCs fail to establish accessible chromatin in selected regions that are enriched for putative enhancers and binding motifs of hematopoietic lineage transcription factors. Our study provides a fundamental mechanistic understanding of the role of Baf155 in hematopoietic lineage chromatin priming and the functional consequences of Baf155 deficiency in regeneration and tumor immunity.
摘要：
染色质引发促进细胞类型特异性基因表达，谱系分化，和发展。染色质引发的机制尚未完全了解。这里,我们报道，缺乏BAF（BRG1/BRM相关因子）染色质重塑复合物的Baf155亚基的小鼠造血干细胞和祖细胞（HSPCs）产生的成熟血细胞数量显着减少，导致移植后造血再生失败和5-氟尿嘧啶（5-FU）损伤。Baf155缺陷型HSPC产生的中性粒细胞特别少，B细胞,和体内稳态的CD8+T细胞，支持更具免疫抑制性的肿瘤微环境并增强肿瘤生长。单核多组学分析显示，Baf155缺陷型HSPC无法在富含推定增强子和造血谱系转录因子结合基序的选定区域中建立可接近的染色质。我们的研究提供了对Baf155在造血谱系染色质引发中的作用以及Baf155缺乏在再生和肿瘤免疫中的功能后果的基本机制理解。
