A distal intergenic region controls pancreatic endocrine differentiation by acting as a transcriptional enhancer and as a polycomb response element

• Published in: PloS one 2017-02, Vol.12 (2), p.e0171508-e0171508
• Main Authors: van Arensbergen, Joris, Dussaud, Sebastien, Pardanaud-Glavieux, Corinne, García-Hurtado, Javier, Sauty, Claire, Guerci, Aline, Ferrer, Jorge, Ravassard, Philippe
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Binding sites; Bioinformatics; Biology and Life Sciences; Cell activation; Cell Differentiation - genetics; Deoxyribonucleic acid; Developmental stages; Diabetes; Differentiation; DNA; DNA binding proteins; Drosophila; Embryonic development; Enhancers; Gene expression; Gene sequencing; Genetic aspects; Genomes; Growth factors; Human health and pathology; Insects; Integrated software; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Laboratories; Life Sciences; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pancreas; Polycomb group proteins; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Proteins; Recruitment; Regulatory sequences; Research and Analysis Methods; Response Elements - genetics; Stem cells; Studies; Transcription (Genetics); Transcription factors; Vertebrates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171508

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.