RT Journal Article
SR Electronic
T1 Notch Controls Multiple Pancreatic Cell Fate Regulators Through Direct Hes1-mediated Repression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 336305
DO 10.1101/336305
A1 Kristian H. de Lichtenberg
A1 Philip A. Seymour
A1 Mette C. Jørgensen
A1 Yung-Hae Kim
A1 Anne Grapin-Botton
A1 Mark A. Magnuson
A1 Nikolina Nakic
A1 Jorge Ferrer
A1 Palle Serup
YR 2018
UL http://biorxiv.org/content/early/2018/06/01/336305.abstract
AB Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq analysis of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks associated with 354 genes. Among these were genes important for tip/trunk segregation such as Ptf1a and Nkx6-1, genes involved in endocrine differentiation such as Insm1 and Dll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as Neurog2 and Ascl1. Surprisingly, we find that Hes1 binds a large number of loci previously reported to bind Ptf1a, including a site downstream of the Nkx6-1 gene. Notably, we find a number of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently of Neurog3 function, including the tip progenitor/acinar genes; Ptf1a, Gata4, Bhlha15, and Gfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new molecular targets of Notch signaling that may be important for controlling cell fate choices in pancreas development.