Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
CIBERONC, Madrid, Spain.
Nat Commun. 2023 Jun 23;14(1):3761. doi: 10.1038/s41467-023-39291-x.
Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.
胰腺腺泡细胞依赖 PTF1 和其他转录因子来部署其转录程序。我们确定 NFIC 是 NR5A2 的相互作用因子和腺泡分化的调节剂。NFIC 结合位点在 NR5A2 ChIP-Seq 峰中富集。Nfic 敲除小鼠的胰腺较小，组织学正常，但腺泡基因表达减少。NFIC 结合并调节腺泡基因和涉及 RNA/蛋白质代谢的基因的启动子，Nfic 敲除胰腺显示核糖体 RNA 成熟缺陷。NFIC 通过结合基因启动子来抑制内质网应激程序，并且是解决 Tunicamycin 介导的应激所必需的。NFIC 在鹅膏蕈碱诱导的胰腺炎期间下调，并且在损伤后恢复时是必需的。正常的人类胰腺中 NFIC 转录本水平较低，显示出 Nfic 敲除小鼠中下调的基因表达减少。NFIC 在小鼠和人类胰腺导管腺癌中的表达下调。一致地，Nfic 敲除小鼠发展出更多的突变 Kras 驱动的前瘤病变。
