Identification and analysis of murine pancreatic islet enhancers

• Published in: Diabetologia Vol. 56; no. 3; pp. 542 - 552
• Main Authors: Tennant, B. R., Robertson, A. G., Kramer, M., Li, L., Zhang, X., Beach, M., Thiessen, N., Chiu, R., Mungall, K., Whiting, C. J., Sabatini, P. V., Kim, A., Gottardo, R., Marra, M. A., Lynn, F. C., Jones, S. J. M., Hoodless, P. A., Hoffman, B. G.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2013; Springer; Springer Nature B.V
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cancer; Chromatin Immunoprecipitation; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enhancer Elements, Genetic - genetics; Epigenetics; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fibrosarcoma; Gene expression; Genomes; Health sciences; Hepatocyte Nuclear Factor 3-beta - metabolism; Homeodomain Proteins - metabolism; Human Physiology; Insulin; Internal Medicine; Islets of Langerhans - metabolism; Medical research; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Nerve Tissue Proteins - metabolism; Ontology; Proteins; Stem cells; Trans-Activators - metabolism; Transcription factors; British Columbia Canada; Canada; United States > US; ChIP-seq; lncRNA; Enhancer; H3K4me1; Pancreas; Transcription factor; Endocrinopathy; Diabetes mellitus
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2797-5

Aims/hypothesis 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/interpretations 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.