東海大学医学部基礎医学系生体防御学Department of Immunology, Tokai University School of Medicine― 52 ―RUNX transcription factors are essential for Notch-mediated early T cell development. Here, we examined functional differences in RUNX1 between lymphoid progenitors (LPs) and uncommitted T progenitors (TPs) before and after Notch stimulation. Transcriptome analysis of Cbfb-deficient LPs and TPs using Cas9-expressing Ebf1-deficient LP cell lines revealed that the majority of RUNX/Cbfb-regulated genes were developmental stage-specific. Interestingly, many T-signature genes were repressed by RUNX/Cbfb in LPs, while they were activated by RUNX/Cbfb in Notch-stimulated TPs. Proteomics analysis of RUNX1 interacting molecules in LPs and TPs identified the transcriptional repressor CTCF as a LP-specific binding partner of RUNX1. In addition, dynamic binding site switching of RUNX1 across the genome was observed before and after Notch stimulation. The CTCF motif was highly enriched in LP-specific RUNX1 binding genomic regions, while it disappeared in TP-specific RUNX1 binding regions. Surprisingly, both Cbfb-deficient LPs and primary BM progenitors generated CD25+ DN2-like cells without Notch stimulation. These results were repeated in both Ctcf disrupted cells. Moreover, the transcriptome analysis of Ctcf-deficient LPs revealed that the earliest Notch target genes, Tcf7 and Hes1, were repressed by CTCF. Thus, the RUNX1/CTCF complex would suppress spontaneous activation of T-signature genes in LPs, and Notch-mediated dissociation of RUNX1 from the CTCF complex is involved in the activation of these genes. Therefore, Notch-mediated functional conversion of RUNX transcription factors plays a significant role in the initiation of the T-lineage program.AbstractNotch-dependent…functional…conversion…of…RUNX…transcription…factors…regulates…the…initiation…of発生段階特異的なクロマチン構造を確立するRUNX転写因子の機能解析と疾患制御…T-lineage…programHiroyuki Hosokawa細川 裕之
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