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| Status |
Public on Jun 17, 2015 |
| Title |
Acute TNF-induced repression of cell identity genes is mediated by NFkB-directed redistribution of cofactors from super-enhancers |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), is directly involved and required for the acute activation of the inflammatory gene program. Here we show that the major transactivating subunit of NF?B, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high occupancy sites within super-enhancers. Based on these data we have developed models that with high accuracy predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell type-specific manner. Our results propose a novel paradigm for NF?B-mediated repression, whereby NF?B selectively redistributes cofactors from high occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes.
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| Overall design |
Genome-wide assesment of the acute transcriptional response to TNF in human SGBS adipocytes using RNA- ChIP- and DHS-seq. Total RNA-seq and RNAPII-ChIP seq for vehicle and TNF treated adipocytes are available under GSE60462
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| Contributor(s) |
Fisker Schmidt S, Ditlev Larsen B, Loft A, Nielsen R, Grud Skat Madsen J, Mandrup S |
| Citation(s) |
26113076 |
| |
| Submission date |
Dec 16, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Susanne Mandrup |
| E-mail(s) |
s.mandrup@bmb.sdu.dk
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| Phone |
+45 6550 2340
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| Organization name |
University of Southern Denmark
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| Department |
Biochemistry and Molecular Biology
|
| Street address |
Campusvej 55
|
| City |
Odense M |
| ZIP/Postal code |
5230 |
| Country |
Denmark |
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| Platforms (1) |
| GPL18460 |
Illumina HiSeq 1500 (Homo sapiens) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA270506 |
| SRA |
SRP051211 |
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