title: Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis.
abstract: Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Sona
authors.initials: S
authors.lastname: Kang
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Linus T
authors.initials: LT
authors.lastname: Tsai
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Evertts
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Xu
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Griffin
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Robbyn
authors.initials: R
authors.lastname: Issner
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Whitton
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Epstein
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.affiliation: 1] Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Broad Institute, Cambridge, Massachusetts 02142, USA [3] Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Rosen
mesh_terms: D016475:3T3 Cells; D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D057890:Epigenomics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000473:pathology; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D051996:Transcription Factor RelA / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D006657:Histones; D007328:Insulin; D018167:Receptors, Calcitriol; D011965:Receptors, Glucocorticoid; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone