TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.
The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.
Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Inês
I
Cebola
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.|Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
Santiago A
SA
Rodríguez-Seguí
Wellcome Trust and MRC Stem Cells Centre, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery and Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, United Kingdom.
Candy H-H
CH
Cho
Instituto de Biologia Molecular e Celular (IBMC), 4150-180 Porto, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
José
J
Bessa
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Meritxell
M
Rovira
Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, 41013 Sevilla, Spain.
Mario
M
Luengo
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
Mariya
M
Chhatriwala
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical & Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom.
Andrew
A
Berry
Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Joan
J
Ponsa-Cobas
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Miguel Angel
MA
Maestro
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical & Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom.
Rachel E
RE
Jennings
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Lorenzo
L
Pasquali
Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Ignasi
I
Morán
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Natalia
N
Castro
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical & Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom.|Endocrinology Department, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, United Kingdom.
Neil A
NA
Hanley
Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, 41013 Sevilla, Spain.
Jose Luis
JL
Gomez-Skarmeta
Wellcome Trust and MRC Stem Cells Centre, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery and Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
Ludovic
L
Vallier
Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.|Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Jorge
J
Ferrer
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D038081:Organogenesis; D010179:Pancreas / Q000196:embryology / Q000378:metabolism*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human