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| Status |
Public on Jan 23, 2017 |
| Title |
PARP-1 Controls the Adipogenic Transcriptional Program by PARylating C/EBPβ and Modulating Its Transcriptional Activity |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Poly(ADP-ribosyl)ation (PARylation) is a regulatory post-translational modification of proteins mediated by PARP family members, such as PARP-1. Although PARP-1 and PARylation have been widely studied, very few examples of definitive biological roles for site-specific PARylation of proteins exist in the literature. Here we show that C/EBPβ, a key pro-adipogenic transcription factor, is PARylated by PARP-1 at Glu135, as well as two adjacent amino acids (K133 and E139). PARylation at these sites inhibits C/EBPβ’s DNA binding and transcriptional activities, and attenuates adipogenesis in various cell-based models of adipogenesis. Interestingly, PARP-1 catalytic activity drops precipitously during the first 48 hours of hormone-induced differentiation, corresponding to a release of C/EBPβ from PARylation-mediated inhibition. This allows the binding of C/EBPβ to the promoters of pro-adipogenic target genes (e.g., Cebpa, Pparg2), their subsequent expression, and continued differentiation. In this regard, depletion of PARP-1 or chemical inhibition of its catalytic activity enhances early adipogenic events. Collectively, our results provide a clear example of how site-specific PARylation of a key transcription factor can affect its molecular and biochemical functions, as well as the biological outcomes that it controls.
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| Overall design |
ChIP-seq (C/EBP beta) were perfomed in 3T3-L1 cells expressing doxycycline inducible HA tagged C/EBP beta LAP wildtype and PARylation site mutant, with or without doxycycline and PARP inhibitor treatment.
|
| Web link |
http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30723-7
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| |
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| Contributor(s) |
Luo X, Ryu KW, Kim D, Nandu T, Kraus LW |
| Citation(s) |
28107648 |
| Submission date |
Aug 02, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
W. Lee Kraus |
| E-mail(s) |
lee.kraus@utsouthwestern.edu
|
| Organization name |
UT Southwestern Medical Center
|
| Street address |
5323 Harry Hines Blvd.
|
| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75390-8511 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA336169 |
| SRA |
SRP080809 |
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