title: Pancreatic β cell enhancers regulate rhythmic transcription of genes controlling insulin secretion.
abstract: The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic β cell function, we examined pancreatic islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery and signaling factors that regulate insulin release. CLOCK/BMAL1 colocalized with the pancreatic transcription factor PDX1 within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. We also found that β cell clock ablation in adult mice caused severe glucose intolerance. Thus, cell type-specific enhancers underlie the circadian control of peripheral metabolism throughout life and may help to explain its dysregulation in diabetes.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Perelis
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Biliana
authors.initials: B
authors.lastname: Marcheva
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Kathryn Moynihan
authors.initials: KM
authors.lastname: Ramsey
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipma
authors.affiliation: Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA. Graduate Program in the Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA. James Franck Institute, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hutchison
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Clara Bien
authors.initials: CB
authors.lastname: Peek
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Omura
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Allred
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 52705, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
authors.affiliation: Graduate Program in the Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA. James Franck Institute, University of Chicago, Chicago, IL 60637, USA. Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Dinner
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. j-bass@northwestern.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bass
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005089:Exocytosis / Q000235:genetics; D005786:Gene Expression Regulation; D018149:Glucose Intolerance; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D056926:CLOCK Proteins; C538944:Clock protein, mouse