PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells.

Autor:	Teo AK; Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore., Tsuneyoshi N; Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore., Hoon S; Molecular Engineering Lab, A(∗)STAR, 61 Biopolis Drive, Proteos #03-13, Singapore 138673, Singapore., Tan EK; Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore., Stanton LW; Genome Institute of Singapore, A(∗)STAR, 60 Biopolis Street, #02-01 Genome, Singapore 138672, Singapore., Wright CV; Department of Cell and Developmental Biology and Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, 3144 MRBIII, 465 21(st) Avenue South, Nashville, TN 37232, USA., Dunn NR; Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore. Electronic address: ray.dunn@imb.a-star.edu.sg.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2015 Apr 14; Vol. 4 (4), pp. 578-90. Date of Electronic Publication: 2015 Apr 02.
DOI:	10.1016/j.stemcr.2015.02.015
Abstrakt:	Inactivation of the Pancreatic and Duodenal Homeobox 1 (PDX1) gene causes pancreatic agenesis, which places PDX1 high atop the regulatory network controlling development of this indispensable organ. However, little is known about the identity of PDX1 transcriptional targets. We simulated pancreatic development by differentiating human embryonic stem cells (hESCs) into early pancreatic progenitors and subjected this cell population to PDX1 chromatin immunoprecipitation sequencing (ChIP-seq). We identified more than 350 genes bound by PDX1, whose expression was upregulated on day 17 of differentiation. This group included known PDX1 targets and many genes not previously linked to pancreatic development. ChIP-seq also revealed PDX1 occupancy at hepatic genes. We hypothesized that simultaneous PDX1-driven activation of pancreatic and repression of hepatic programs underlie early divergence between pancreas and liver. In HepG2 cells and differentiating hESCs, we found that PDX1 binds and suppresses expression of endogenous liver genes. These findings rebrand PDX1 as a context-dependent transcriptional repressor and activator within the same cell type. (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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