Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids. Cell Metab 2021 Aug 03;33(8):1592-1609.e7
Date
07/08/2021Pubmed ID
34233159Pubmed Central ID
PMC8340270DOI
10.1016/j.cmet.2021.06.004Scopus ID
2-s2.0-85111276882 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
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.
Author List
Hu W, Jiang C, Kim M, Yang W, Zhu K, Guan D, Lv W, Xiao Y, Wilson JR, Rader DJ, Pui CH, Relling MV, Lazar MAAuthor
Yang Xiao Assistant Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdipocytesAnti-Inflammatory Agents
Dexamethasone
Epigenomics
Glucocorticoids
Humans
Receptors, Glucocorticoid
