HNF1B型
生物
重编程
爪蟾
异位表达
细胞生物学
转录因子
遗传学
诱导多能干细胞
6号乘客
清脆的
肝细胞核因子
基因
胚胎干细胞
同源盒
作者
Kelli Grand,Martine Stoltz,Ludovica Rizzo,Ruth Röck,Michael M. Kaminski,Gabriela Salinas,Maike Getwan,Thomas Naert,Roman Pichler,Soeren S. Lienkamp
出处
期刊:Journal of The American Society of Nephrology
日期:2022-12-15
被引量:13
标识
DOI:10.1681/asn.2022010076
摘要
Background Hepatocyte nuclear factor-1 beta (HNF1B) is an essential transcription factor during embryogenesis. Mutations in HNF1B are the most common monogenic causes of congenital cystic dysplastic renal malformations. The direct functional consequences of mutations in HNF1B on its transcriptional activity are unknown. Methods Direct reprogramming of mouse fibroblasts to induced renal tubular epithelial cells was conducted both with wild-type HNF1B and with patient mutations. HNF1B was expressed in Xenopus ectodermal explants. Transcriptomic analysis by bulk RNA-Seq identified conserved targets with differentially regulated expression by the wild-type or R295C mutant. CRISPR/Cas9 genome editing in Xenopus embryos evaluated transcriptional targets in vivo . Results HNF1B is essential for reprogramming mouse fibroblasts to induced renal tubular epithelial cells and induces development of ectopic renal organoids from pluripotent Xenopus cells. The mutation R295C retains reprogramming and inductive capacity but alters the expression of specific sets of downstream target genes instead of diminishing overall transcriptional activity of HNF1B. Surprisingly, targets associated with polycystic kidney disease were less affected than genes affected in congenital renal anomalies. Cross-species–conserved transcriptional targets were dysregulated in hnf1b CRISPR-depleted Xenopus embryos, confirming their dependence on hnf1b . Conclusions HNF1B activates an evolutionarily conserved program of target genes that disease-causing mutations selectively disrupt. These findings provide insights into the renal transcriptional network that controls nephrogenesis.
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