title: Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates.
abstract: Embryonic development relies on the capacity of progenitor cells to appropriately respond to inductive cues, a cellular property known as developmental competence. Here, we report that epigenetic priming of enhancers signifies developmental competence during endodermal lineage diversification. Chromatin mapping during pancreatic and hepatic differentiation of human embryonic stem cells revealed the en masse acquisition of a poised chromatin state at enhancers specific to endoderm-derived cell lineages in gut tube intermediates. Experimentally, the acquisition of this poised enhancer state predicts the ability of endodermal intermediates to respond to inductive signals. Furthermore, these enhancers are first recognized by the pioneer transcription factors FOXA1 and FOXA2 when competence is acquired, while subsequent recruitment of lineage-inductive transcription factors, such as PDX1, leads to enhancer and target gene activation. Together, our results identify the acquisition of a poised chromatin state at enhancers as a mechanism by which progenitor cells acquire developmental competence.
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Ruiyu
authors.initials: R
authors.lastname: Xie
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harper
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Nisha A
authors.initials: NA
authors.lastname: Patel
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Kayla
authors.initials: K
authors.lastname: Muth
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Palmer
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Yunjiang
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Dieter K
authors.initials: DK
authors.lastname: Lam
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Institute for Diabetes, Obesity and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Raum
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Institute for Diabetes, Obesity and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0761, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0653, USA. Electronic address: biren@ucsd.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0761, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0653, USA. Electronic address: masander@ucsd.edu.
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D053595:Embryonic Stem Cells / Q000502:physiology*; D004707:Endoderm / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D005775:Gastrula / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009928:Organ Specificity / Q000235:genetics; D010179:Pancreas / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D015415:Biomarkers; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D051542:Hepatocyte Nuclear Factor 3-beta
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