Histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers

• 成果类型: Article
• 署名作者: Kazerani, Maryam; Cernilogar, Filippo; Pasquarella, Alessandra; Hinterberger, Maria; Nuber, Alexander; Klein, Ludger; Schotta, Gunnar
• 署名单位: Bavarian Nordic; University of Munich; University of Eastern Piedmont Amedeo Avogadro; University of Munich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12020
• DOI: 10.1073/pnas.2409656121
• 发表日期: 2024-12-24
• 关键词: stem-cells; endogenous retroviruses; progenitor cells; dna methylation; self-renewal; expression; ELEMENTS; genes; pu.1; eset

摘要

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.