|
| Status |
Public on Jan 11, 2019 |
| Title |
Patient adipose stem cell-derived adipocytes reveal genetic variation that predicts anti-diabetic drug response |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
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
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| |
|
| Overall design |
hACSs derived from obstity patient were differentiated into adipocytes; then treated with rosiglitazone
|
| Web link |
https://www.med.upenn.edu/lazarlab/
|
| |
|
| Contributor(s) |
Hu W, Jiang C |
| Citation(s) |
30639037 |
| |
| Submission date |
Jun 06, 2018 |
| Last update date |
Nov 20, 2020 |
| Contact name |
Chunjie Jiang |
| E-mail(s) |
[email protected]
|
| Phone |
2153164211
|
| Organization name |
University of Pennsylvania
|
| Department |
Institute for Diabetes, Obesity, and Metabolism
|
| Lab |
Mitchell A. Lazar
|
| Street address |
3400 Civic Center Boulevard
|
| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
| |
|
| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (62)
|
|
| Relations |
| BioProject |
PRJNA474921 |
| SRA |
SRP149925 |
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