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Status |
Public on Feb 27, 2024 |
Title |
Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407 |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such as GLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 ChIP-seq peaks significantly overlapped with PPARγ ChIP-seq peaks, with more than half of ZFP407 peaks overlapping with PPARγ peaks. Transcription factor binding motifs enriched in these overlapping sites included CTCF, RARα/RXRγ, TP73, and ELK1, which regulate cellular development and function within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 domains potentially necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 ChIP-seq analyses identified regions that did not overlap with PPARγ peaks. These non-overlapping peaks were significantly enriched for the transcription factor binding motifs of TBX19, PAX8, HSF4, and ZKSCAN3, which may contribute to the PPARγ-independent functions of ZFP407 in adipocytes and other cell types.
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Overall design |
Chromatin Immunoprecipitation DNA Sequencing (ChIP-Seq) of Zfp407 in differentiated 3T3-L1 adipocytes
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Web link |
https://doi.org/10.1371/journal.pone.0294003
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Contributor(s) |
Charrier A, Ockunzzi J, Main LR, Ghanta SV, Buchner DA |
Citation(s) |
38781157 |
NIH grant(s) |
Grant ID |
Grant title |
Affiliation |
Name |
R01 DK119305 |
Role of adipocyte gene expression regulation by Zfp407 in adipocyte biology and metabolic disease |
CASE WESTERN RESERVE UNIVERSITY |
David A Buchner |
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Submission date |
Oct 20, 2023 |
Last update date |
May 24, 2024 |
Contact name |
David Buchner |
E-mail(s) |
dab22@case.edu
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Organization name |
Case Western Reserve University
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Department |
Genetics and Genome Sciences
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Street address |
10900 Euclid Ave
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City |
Cleveland |
State/province |
OH |
ZIP/Postal code |
44106 |
Country |
USA |
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Platforms (1) |
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Samples (1) |
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Relations |
BioProject |
PRJNA1030295 |
Supplementary file |
Size |
Download |
File type/resource |
GSE245861_RAW.tar |
130.0 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
Raw data are available in SRA |
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