title: Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation.
abstract: Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Olivia
authors.initials: O
authors.lastname: Alder
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cullum
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Lee
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Arohumam C
authors.initials: AC
authors.lastname: Kan
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Yuyin
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Garside
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Misha
authors.initials: M
authors.lastname: Bilenky
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: A Sorana
authors.initials: AS
authors.lastname: Morrissy
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Robertson
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A1S6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z4H4, Canada.
authors.forename: Steven J M
authors.initials: SJM
authors.lastname: Jones
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z4H4, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z4H4, Canada. Electronic address: hoodless@bccrc.ca.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hoodless
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D015870:Gene Expression; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D000090683:Hippo Signaling Pathway; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C496503:Foxa2 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; D017346:Protein Serine-Threonine Kinases