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Notch-dependent and -independent functions of transcription factor RBPJ
Nucleic Acids Research ( IF 14.9 ) Pub Date : 2022-07-18 , DOI: 10.1093/nar/gkac601
Tobias Friedrich 1, 2 , Francesca Ferrante 1 , Léo Pioger 3 , Andrea Nist 4 , Thorsten Stiewe 4 , Jean-Christophe Andrau 3 , Marek Bartkuhn 2, 5 , Benedetto Daniele Giaimo 1 , Tilman Borggrefe 1
Affiliation  

Signal transduction pathways often involve transcription factors that promote activation of defined target gene sets. The transcription factor RBPJ is the central player in Notch signaling and either forms an activator complex with the Notch intracellular domain (NICD) or a repressor complex with corepressors like KYOT2/FHL1. The balance between these two antagonizing RBPJ-complexes depends on the activation state of the Notch receptor regulated by cell-to-cell interaction, ligand binding and proteolytic cleavage events. Here, we depleted RBPJ in mature T-cells lacking active Notch signaling and performed RNA-Seq, ChIP-Seq and ATAC-seq analyses. RBPJ depletion leads to upregulation of many Notch target genes. Ectopic expression of NICD1 activates several Notch target genes and enhances RBPJ occupancy. Based on gene expression changes and RBPJ occupancy we define four different clusters, either RBPJ- and/or Notch-regulated genes. Importantly, we identify early (Hes1 and Hey1) and late Notch-responsive genes (IL2ra). Similarly, to RBPJ depletion, interfering with transcriptional repression by squelching with cofactor KYOT2/FHL1, leads to upregulation of Notch target genes. Taken together, RBPJ is not only an essential part of the Notch co-activator complex but also functions as a repressor in a Notch-independent manner.

中文翻译:

转录因子 RBPJ 的缺口依赖性和非依赖性功能

信号转导途径通常涉及促进特定靶基因组激活的转录因子。转录因子 RBPJ 是 Notch 信号传导的核心参与者,它要么与 Notch 胞内结构域 (NICD) 形成激活复合物,要么与 KYOT2/FHL1 等辅助阻遏物形成阻遏复合物。这两种拮抗 RBPJ 复合物之间的平衡取决于由细胞间相互作用、配体结合和蛋白水解切割事件调节的 Notch 受体的激活状态。在这里,我们耗尽了缺乏活性 Notch 信号传导的成熟 T 细胞中的 RBPJ,并进行了 RNA-Seq、ChIP-Seq 和 ATAC-seq 分析。RBPJ 耗竭导致许多 Notch 靶基因的上调。NICD1 的异位表达激活几个 Notch 靶基因并增强 RBPJ 占用。基于基因表达变化和 RBPJ 占有率,我们定义了四个不同的簇,RBPJ 和/或 Notch 调节基因。重要的是,我们确定了早期(Hes1 和 Hey1)和晚期 Notch 响应基因(IL2ra)。类似地,对于 RBPJ 耗竭,通过用辅因子 KYOT2/FHL1 压制来干扰转录抑制,导致 Notch 靶基因的上调。总之,RBPJ 不仅是 Notch 共激活复合物的重要组成部分,而且还以独立于 Notch 的方式作为阻遏物发挥作用。
更新日期:2022-07-18
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