title: Identification and analysis of murine pancreatic islet enhancers.
abstract: OBJECTIVE
  The paucity of information on the epigenetic barriers that are blocking reprogramming protocols, and on what makes a beta cell unique, has hampered efforts to develop novel beta cell sources. Here, we aimed to identify enhancers in pancreatic islets, to understand their developmental ontologies, and to identify enhancers unique to islets to increase our understanding of islet-specific gene expression.
  
  
  METHODS
  We combined H3K4me1-based nucleosome predictions with pancreatic and duodenal homeobox 1 (PDX1), neurogenic differentiation 1 (NEUROD1), v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA) and forkhead box A2 (FOXA2) occupancy data to identify enhancers in mouse islets.
  
  
  RESULTS
  We identified 22,223 putative enhancer loci in in vivo mouse islets. Our validation experiments suggest that nearly half of these loci are active in regulating islet gene expression, with the remaining regions probably poised for activity. We showed that these loci have at least nine developmental ontologies, and that islet enhancers predominately acquire H3K4me1 during differentiation. We next discriminated 1,799 enhancers unique to islets and showed that these islet-specific enhancers have reduced association with annotated genes, and identified a subset that are instead associated with novel islet-specific long non-coding RNAs (lncRNAs).
  
  
  CONCLUSIONS
  Our results indicate that genes with islet-specific expression and function tend to have enhancers devoid of histone methylation marks or, less often, that are bivalent or repressed, in embryonic stem cells and liver. Further, we identify a subset of enhancers unique to islets that are associated with novel islet-specific genes and lncRNAs. We anticipate that these data will facilitate the development of novel sources of functional beta cell mass.
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital and Sunny Hill Health Centre, Room A4-185, 950 W28th Avenue, Vancouver, BC, Canada V5Z 4H4.
authors.forename: B R
authors.initials: BR
authors.lastname: Tennant
authors.forename: A G
authors.initials: AG
authors.lastname: Robertson
authors.forename: M
authors.initials: M
authors.lastname: Kramer
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Beach
authors.forename: N
authors.initials: N
authors.lastname: Thiessen
authors.forename: R
authors.initials: R
authors.lastname: Chiu
authors.forename: K
authors.initials: K
authors.lastname: Mungall
authors.forename: C J
authors.initials: CJ
authors.lastname: Whiting
authors.forename: P V
authors.initials: PV
authors.lastname: Sabatini
authors.forename: A
authors.initials: A
authors.lastname: Kim
authors.forename: R
authors.initials: R
authors.lastname: Gottardo
authors.forename: M A
authors.initials: MA
authors.lastname: Marra
authors.forename: F C
authors.initials: FC
authors.lastname: Lynn
authors.forename: S J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: P A
authors.initials: PA
authors.lastname: Hoodless
authors.forename: B G
authors.initials: BG
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C496503:Foxa2 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C093564:Neurogenic differentiation factor 1