Dataset Information

Patient adipose stem cell-derived adipocytes reveal genetic variation that predicts anti-diabetic drug response

ABSTRACT: Thiazolidinedione drugs (TZDs) target the transcriptional activity of PPARg to reverse insulin resistance in type 2 diabetes, but side effects limit their clinical use. Here, using human adipose stem cell-derived adipocytes, we demonstrate that single-nucleotide polymorphisms (SNPs) were enriched at sites of patient-specific PPARg binding, which correlated with the individual-specific effects of TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPARg binding by influencing the genomic occupancy of its cooperating factor NFIA. Conversion of rs4743771 from the inactive SNP allele to the active one by CRISPR/Cas9-mediated editing rescued PPARg binding as well as rosi-induction of ABCA1 expression. Moreover, rs4743771 is a major determinant of undesired serum cholesterol increases in rosi-treated diabetics. These data highlight human genetic variation that impacts PPARg genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders

ORGANISM(S): Homo sapiens

PROVIDER: GSE115421 | GEO | 2019/01/11

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Rosiglitazone (Rosi), a member of the thiazolidinedione class of drugs used to treat type 2 diabetes, activates the adipocyte-specific transcription factor peroxisome proliferator-activated receptor gamma (PPARg). This activation causes bone loss in animals and humans, at least in part due to suppression of osteoblast differentiation from marrow mesenchymal stem cells (MSC). In order to identify mechanisms by which PPARg2 suppresses osteoblastogenesis and promotes adipogenesis in MSC, we have analyzed the PPARg2 transcriptome in response to Rosi. A total of 4,252 transcriptional changes resulted when Rosi (1 uM) was applied to the U-33 marrow stromal cell line, stably transfected with PPARg2 (U-33/g2), as compared to non-induced U-33/g2 cells. Differences between U-33/g2 and U-33 cells stably transfected with empty vector (U-33/c) comprised 7,928 transcriptional changes, independent of Rosi. Cell type-, time- and treatment-specific gene clustering uncovered distinct patterns of PPARg2 transcriptional control of MSC lineage commitment. The earliest changes accompanying Rosi activation of PPARg2 included adjustments in morphogenesis, Wnt signaling, and immune responses, as well as sustained induction of lipid metabolism. Expression signatures influenced by longer exposure to Rosi provided evidence for distinct mechanisms governing the repression of osteogenesis and stimulation of adipogenesis. Our results suggest interactions that could lead to the identification of a “master” regulatory scheme controlling osteoblast differentiation. Keywords: rosiglitazone, PPARgamma, microarray, time course, gene expression, stem cells U-33/g2 and U-33/c cells were cultured in the presence or absence of Rosi and gene expression was monitored at three different time points (2, 24, 72h) after exposure to the agonist. Each time point corresponds to a separate stage of Rosi-treated U-33/g2 cell conversion from the osteoblast-like phenotype to the adipocyte-like phenotype and includes induction (2h), intermediate alterations in phenotype progression (24h), and a terminally differentiated adipocytic with completely suppressed osteoblastic phenotype (72h). The experiment is a full factorial design performed in replicate.

Dataset Information

Patient adipose stem cell-derived adipocytes reveal genetic variation that predicts anti-diabetic drug response

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure