HNF4a acts as upstream functional regulator of intestinal Wnt3 and Paneth cell fate

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. mRNA profiles of DMSO-treated (Control) and 4OHT-treated (Hnf4a-depleted) jejunal organoids, also treated with recombinant Wnt3A, at day 2 (3 replicates/condition)