HNF4a acts as upstream functional regulator of intestinal Wnt3 and Paneth cell fate [RNA-seq]. HNF4a acts as upstream functional regulator of intestinal Wnt3 and Paneth cell fate [RNA-seq]

Maturation of Paneth cells depends on canonical Wnt signaling, but few transcriptional regulators have been identified to this end. We showed that HNF4a plays a non-redundant and crucial role in supporting the growth and survival of small intestinal epithelial cultures when cultured ex vivo as organoids. Transcriptomic analyses revealed an autosomal function of HNF4a in Wnt3 transcriptional regulation and Paneth cell differentiation. We showed that Wnt3a supplementation reversed cell death and transcriptional changes caused by the deletion of Hnf4a in jejunal organoids. Overall design: mRNA profiles of DMSO-treated (Control) and 4OHT-treated (Hnf4a-depleted) jejunal organoids at day 2 and 4 (4 replicates/condition)

潘氏细胞（Paneth cells）的成熟依赖于经典Wnt信号通路（canonical Wnt signaling），但目前针对该过程已鉴定的转录调控因子（transcriptional regulators）仍寥寥无几。本研究证实，肝细胞核因子4α（HNF4α）在体外培养的小肠上皮类器官（organoids）中，对维持上皮细胞的生长与存活发挥着不可替代且至关重要的作用。转录组分析（transcriptomic analyses）结果显示，肝细胞核因子4α在Wnt3的转录调控与潘氏细胞分化过程中具备常染色体调控功能。研究进一步证实，在空肠类器官中补充Wnt3a，可逆转因Hnf4α敲除所导致的细胞死亡及转录组表达异常。实验整体设计：分别在培养第2天和第4天，采集经二甲基亚砜（DMSO）处理的对照组与经4-羟基他莫昔芬（4OHT）处理的Hnf4α缺失组空肠类器官样本，开展mRNA表达谱（mRNA profiles）分析，每组设置4个生物学重复。