Acute TNF-induced repression of cell identity genes is mediated by NF?B-directed redistribution of cofactors from super-enhancers.

ABSTRACT: 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 ?-light-chain-enhancer of activated B cells (NF?B) 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.

SUBMITTER: Schmidt SF 

PROVIDER: S-EPMC4561488 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature