Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

Abstract

SUMMARY SNPs affecting disease risk often reside in non-coding genomic regions. Here we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof-of-concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

“…Indeed, PPAR␥ bound at the major Rev-erb␣ binding sites at the Klb locus in EWAT (41) (Fig. 5A, purple track).…”

“…A, ChIP-seq profiles of Rev-erb␣ (green tracks, also shown in Fig. 3A) (39,48) and PPAR␥ (purple track) (41) or PPAR␣ (orange track) (42) binding at the Klb locus in, respectively, EWAT or liver of WT mice. The major Rev-erb␣ peak at the Klb locus is highlighted in pink.…”

“…Rev-erb␣ ChIP-seq in EWAT is available under GEO accession number GSE79166. PPAR␥ ChIP-seq in 3T3-L1 is from GEO accession number GSE27450 (40), PPAR␥ ChIP-seq in EWAT is from GEO accession number GSE64458 (41), and PPAR␣ ChIP-seq in liver is from accession number GSE61817 (42). Histone 3 lysine 27 acetylation ChIP-seq in EWAT is from GEO accession number GSE63964 (43).…”

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

“…Multiple lines of evidence have shown that NC mutations can modulate the transcriptional activity and binding of key cell typespecific master transcription factors (TFs) (18,19). In several Mendelian erythroid disorders (MEDs), NC genetic variants have been identified in the DNA-binding motif (WGATAR) of the hematopoietic master regulator, GATA1 (20)(21)(22)(23)(24)(25).…”

“…This difficulty is most clearly reflected in the distribution of mutations listed in databases of Mendelian disorders, such as the Human Gene Mutation Database, where most mutations are found within coding regions (86%) or at intronic splice sites (11%), with only a small fraction (3%) identified in regulatory regions (14). Newer methods for annotating and predicting the impact of noncoding (NC) variants have provided substantial improvements (15, 16), but experimental validation of the presumed effects remains critical for the determination of pathogenicity and elucidation of the mechanism of action (13, 17).Multiple lines of evidence have shown that NC mutations can modulate the transcriptional activity and binding of key cell typespecific master transcription factors (TFs) (18,19). In several Mendelian erythroid disorders (MEDs), NC genetic variants have been identified in the DNA-binding motif (WGATAR) of the hematopoietic master regulator, .…”