title: A distal intergenic region controls pancreatic endocrine differentiation by acting as a transcriptional enhancer and as a polycomb response element.
abstract: Lineage-selective expression of developmental genes is dependent on the interplay between activating and repressive mechanisms. Gene activation is dependent on cell-specific transcription factors that recognize transcriptional enhancer sequences. Gene repression often depends on the recruitment of Polycomb group (PcG) proteins, although the sequences that underlie the recruitment of PcG proteins, also known as Polycomb response elements (PREs), remain poorly understood in vertebrates. While distal PREs have been identified in mammals, a role for positive-acting enhancers in PcG-mediated repression has not been described. Here we have used a highly efficient procedure based on lentiviral-mediated transgenesis to carry out in vivo fine-mapping of, cis-regulatory sequences that control lineage-specific activation of Neurog3, a master regulator of pancreatic endocrine differentiation. Our findings reveal an enhancer region that is sufficient to drive correct spacio-temporal expression of Neurog3 and demonstrate that this same region serves as a PRE in alternative lineages where Neurog3 is inactive.
authors.affiliation: Genomic Programming of Beta-Cells Laboratory, IDIBAPS, Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas, Barcelona, Spain.
authors.forename: Joris
authors.initials: J
authors.lastname: van Arensbergen
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM)-Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Dussaud
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM)-Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Pardanaud-Glavieux
authors.affiliation: Genomic Programming of Beta-Cells Laboratory, IDIBAPS, Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Hurtado
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM)-Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Sauty
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM)-Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Guerci
authors.affiliation: Genomic Programming of Beta-Cells Laboratory, IDIBAPS, Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas, Barcelona, Spain.|Department of Medicine, Imperial Centre for Translational and Experimental Medicine, Imperial College, London, United Kingdom.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM)-Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris, France.
authors.forename: Philippe
authors.identifier: http://orcid.org/0000-0002-0393-9262
authors.initials: P
authors.lastname: Ravassard
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D063146:Polycomb-Group Proteins; C407737:Neurog3 protein, mouse