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Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.
Citation | “Individual-Specific Functional Epigenomics Reveals Genetic Determinants Of Adverse Metabolic Effects Of Glucocorticoids.”. Cell Metabolism, pp. 1592-1609.e7. . |
Center | University of Pennsylvania |
Author | Wenxiang Hu, Chunjie Jiang, Mindy Kim, Wenjian Yang, Kun Zhu, Dongyin Guan, Wenjian Lv, Yang Xiao, Jessica R Wilson, Daniel J Rader, Ching-Hon Pui, Mary Relling V, Mitchell A Lazar |
Keywords | adipocyte, gene regulation, genetic variation, glucocorticoid receptor, hepatocyte, precision medicine |
Abstract |
Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs. |
Year of Publication |
2021
|
Journal |
Cell metabolism
|
Volume |
33
|
Issue |
8
|
Number of Pages |
1592-1609.e7
|
Date Published |
08/2021
|
ISSN Number |
1932-7420
|
DOI |
10.1016/j.cmet.2021.06.004
|
Alternate Journal |
Cell Metab
|
PMID |
34233159
|
PMCID |
PMC8340270
|
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