Differentiation of lineage-committed cells from multipotent progenitors requires the establishment of accessible chromatin at lineage-specific transcriptional enhancers and promoters, which is mediated by pioneer transcription factors that recruit activating chromatin remodeling complexes. Here we show that the Mbd3/nucleosome remodeling and deacetylation (NuRD) chromatin remodeling complex opposes this transcriptional pioneering during B cell programming of multipotent lymphoid progenitors by restricting chromatin accessibility at B cell enhancers and promoters. Mbd3/NuRD-deficient lymphoid progenitors therefore prematurely activate a B cell transcriptional program and are biased toward overproduction of pro–B cells at the expense of T cell progenitors. The striking reduction in early thymic T cell progenitors results in compensatory hyperproliferation of immature thymocytes and development of T cell lymphoma. Our results reveal that Mbd3/NuRD can regulate multilineage differentiation by constraining the activation of dormant lineage-specific enhancers and promoters. In this way, Mbd3/NuRD protects the multipotency of lymphoid progenitors, preventing B cell–programming transcription factors from prematurely enacting lineage commitment. Mbd3/NuRD therefore controls the fate of lymphoid progenitors, ensuring appropriate production of lineage-committed progeny and suppressing tumor formation.

谱系定型细胞与多能祖细胞的分化需要在谱系特异性转录增强子和启动子处建立可接近的染色质，这是由募集激活染色质重塑复合物的先驱转录因子介导的。在这里，我们表明 Mbd3/核小体重塑和去乙酰化 (NuRD) 染色质重塑复合物通过限制 B 细胞增强子和启动子的染色质可及性，在多能淋巴祖细胞的 B 细胞编程过程中反对这种转录先驱。因此，Mbd3/NuRD 缺陷型淋巴祖细胞过早地激活了 B 细胞转录程序，并偏向于以牺牲 T 细胞祖细胞为代价过度生产 pro-B 细胞。早期胸腺 T 细胞祖细胞的显着减少导致未成熟胸腺细胞的代偿性过度增殖和 T 细胞淋巴瘤的发展。我们的结果表明 Mbd3/NuRD 可以通过限制休眠谱系特异性增强子和启动子的激活来调节多谱系分化。通过这种方式，Mbd3/NuRD 保护了淋巴祖细胞的多能性，防止 B 细胞编程转录因子过早地进行谱系定型。Mbd3/NuRD 因此控制淋巴祖细胞的命运，确保适当产生谱系定型后代并抑制肿瘤形成。我们的结果表明 Mbd3/NuRD 可以通过限制休眠谱系特异性增强子和启动子的激活来调节多谱系分化。通过这种方式，Mbd3/NuRD 保护了淋巴祖细胞的多能性，防止 B 细胞编程转录因子过早地进行谱系定型。Mbd3/NuRD 因此控制淋巴祖细胞的命运，确保适当产生谱系定型后代并抑制肿瘤形成。我们的结果表明 Mbd3/NuRD 可以通过限制休眠谱系特异性增强子和启动子的激活来调节多谱系分化。通过这种方式，Mbd3/NuRD 保护了淋巴祖细胞的多能性，防止 B 细胞编程转录因子过早地进行谱系定型。Mbd3/NuRD 因此控制淋巴祖细胞的命运，确保适当产生谱系定型后代并抑制肿瘤形成。