The H3K9me3-specific histone methyltransferase SETDB1 is critical for proper regulation of developmental processes, but the underlying mechanisms are only partially understood. Here, we show that deletion of Setdb1 in mouse fetal liver hematopoietic stem and progenitor cells (HSPCs) results in compromised stem cell function, enhanced myeloerythroid differentiation, and impaired lymphoid development. Notably, Setdb1 -deficient HSPCs exhibit reduced quiescence and increased proliferation, accompanied by the acquisition of a lineage-biased transcriptional program. In Setdb1 -deficient HSPCs, we identify genomic regions that are characterized by loss of H3K9me3 and increased chromatin accessibility, suggesting enhanced transcription factor (TF) activity. Interestingly, hematopoietic TFs like PU.1 bind these cryptic enhancers in wild-type HSPCs, despite the H3K9me3 status. Thus, our data indicate that SETDB1 restricts activation of nonphysiological TF binding sites which helps to ensure proper maintenance and differentiation of fetal liver HSPCs.

中文翻译：

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组蛋白甲基转移酶 SETDB1 通过抑制隐蔽增强子的激活来保护小鼠胎儿造血


H3K9me3 特异性组蛋白甲基转移酶 SETDB1 对于发育过程的适当调节至关重要，但其潜在机制仅部分了解。在这里，我们表明小鼠胎肝造血干细胞和祖细胞 （HSPC） 中 Setdb1 的缺失导致干细胞功能受损、髓红细胞分化增强和淋巴发育受损。值得注意的是，Setdb1 缺陷型 HSPC 表现出静止减少和增殖增加，伴随着谱系偏倚转录程序的获得。在 Setdb1 缺陷型 HSPC 中，我们鉴定了以 H3K9me3 缺失和染色质可及性增加为特征的基因组区域，表明转录因子 （TF） 活性增强。有趣的是，尽管 H3K9me3 状态，但像 PU.1 这样的造血 TF 在野生型 HSPC 中结合这些隐蔽的增强子。因此，我们的数据表明 SETDB1 限制了非生理性 TF 结合位点的激活，这有助于确保胎肝 HSPC 的适当维护和分化。