Dataset Information

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

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.

SUBMITTER: Hu W

PROVIDER: S-EPMC8340270 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

Hu Wenxiang W Jiang Chunjie C Kim Mindy M Yang Wenjian W Zhu Kun K Guan Dongyin D Lv Wenjian W Xiao Yang Y Wilson Jessica R JR Rader Daniel J DJ Pui Ching-Hon CH Relling Mary V MV Lazar Mitchell A MA

Cell metabolism 20210706 8

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 polymorphi ...[more]

PMID: 34233159

Similar Datasets

Project description:BackgroundInsights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits.ResultsUsing 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits.ConclusionsWe systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases.

Dataset Information

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

Publications

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets