Kazerani Maryam, Cernilogar Filippo, Pasquarella Alessandra, Hinterberger Maria, Nuber Alexander, Klein Ludger, Schotta Gunnar
Division of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig Maximilian University Munich, Martinsried 82152, Germany.
Department of Science and Technological Innovation, University of Piemonte Orientale, Alessandria 15121, Italy.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2409656121. doi: 10.1073/pnas.2409656121. Epub 2024 Dec 17.
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 in mouse fetal liver hematopoietic stem and progenitor cells (HSPCs) results in compromised stem cell function, enhanced myeloerythroid differentiation, and impaired lymphoid development. Notably, -deficient HSPCs exhibit reduced quiescence and increased proliferation, accompanied by the acquisition of a lineage-biased transcriptional program. In -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.
H3K9me3特异性组蛋白甲基转移酶SETDB1对发育过程的正常调控至关重要，但其潜在机制仅得到部分理解。在此，我们表明在小鼠胎儿肝脏造血干细胞和祖细胞（HSPCs）中缺失SETDB1会导致干细胞功能受损、髓系红细胞分化增强以及淋巴系发育受损。值得注意的是，SETDB1缺陷的HSPCs表现出静止性降低和增殖增加，并伴随着获得一种谱系偏向的转录程序。在SETDB1缺陷的HSPCs中，我们鉴定出以H3K9me3缺失和染色质可及性增加为特征的基因组区域，提示转录因子（TF）活性增强。有趣的是，尽管存在H3K9me3状态，造血TF如PU.1在野生型HSPCs中仍结合这些隐匿性增强子。因此，我们的数据表明SETDB1限制非生理性TF结合位点的激活，这有助于确保胎儿肝脏HSPCs的正常维持和分化。
