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| Status |
Public on Mar 31, 2018 |
| Title |
BRD4 links carbohydrate and lipid synthetic pathways to a core transcriptional network for a cell-type specific metabolic response (RNA-seq Liver) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glucose and fat metabolism are tightly interconnected where endogenous de novo lipogenesis (DNL) serves to convert carbohydrates directly into lipids. Here, we explored the role of the long isoform Brd4 as a key transcriptional co-activator in lipogenesis. As a member of the Bromo-extraterminal (BET) protein family, Brd4 is characterized by two tandem bromodomains that bind acetylated lysine on both histone and non-histone proteins in chromatin. We found that treatment with MS417, a small molecule inhibitor of Brd4 binding to acetylated lysine, suppresses 3T3-L1 adipocyte differentiation. MS417-treated obese (ob/ob) mice displayed resistance to weight gain and loss of fat from steatotic livers. Comprehensive RNA-seq and ChIP-seq analyses delineate a Brd4-driven gene network required for glycolysis-lipogenesis flux that is shared between glycolytic liver and 3T3-L1 adipocytes, but absent in the non-glycolytic white abdominal fat. Our data further reveal that Brd4 functions to provide specific metabolic resources, such as acetyl-CoA and nicotinamide adenine dinucleotide (NAD) cofactors, in cell types utilizing DNL. Collectively, these findings provide a novel view of the critical role Brd4 plays in orchestrating transcription of a network of genes directing metabolic pathways governing carbohydrate fueled lipid metabolism fundamental for controlling glucose homeostasis and body weight.
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| Overall design |
RNA-seq was used to measure gene expression levels in livers of DMSO (control) and MS417 treated ob/ob (C57BL/6-Lepo) mice.
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| Contributor(s) |
Benko S, Zhang F, Andino B, Zhang G, Li S, Gillespie V, Shin AC, Aguilo F, Chen C, Zhang W, Buettner C, Zhou M, Walsh MJ |
| Citation missing |
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| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA154809 |
Non-coding RNAs for Epigenetic Transcriptional Silencing in Prostate Cancer |
MOUNT SINAI SCHOOL OF MEDICINE |
Martin John Walsh, Zhou |
| R01 HL103967 |
Chromatin Dynamics of the CFTR locus |
MOUNT SINAI SCHOOL OF MEDICINE |
Martin John Walsh |
|
| Submission date |
Jul 07, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Martin J. Walsh |
| E-mail(s) |
martin.walsh@mssm.edu
|
| Organization name |
Mount Sinai School of Medicine
|
| Department |
Structural and Chemical Biology
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| Street address |
One Gustave L. Levy Pl.
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (1) |
| GPL9185 |
Illumina Genome Analyzer (Mus musculus) |
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| Samples (5)
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| This SubSeries is part of SuperSeries: |
| GSE59162 |
BRD4 directs glycolytic metabolism through a comprehensive epigenomic and transcriptional network |
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| Relations |
| BioProject |
PRJNA254511 |
| SRA |
SRP044119 |
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