Acute TNF-induced repression of cell identity genes is mediated by NFκB-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 κ-light-chain-enhancer of activated B cells (NFκB) is directly involved and required for the acute activation of the inflammatory gene program. Here, we show that the major transactivating subunit of NFκB, 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 NFκB-mediated repression, whereby NFκB selectively redistributes cofactors from high-occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes.

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

“…RELA-bound "super-enhancers" have been implicated in the inflammatory response (Brown et al 2014;Schmidt et al 2015). However, it is very likely that many such clusters will not act as a single unit (Hay et al 2016;Shin et al 2016), and we find many of them carrying both "with" and "without" peaks (Supplemental Fig.…”

“…The inflammatory response is characterized by rapid changes in RNA synthesis occurring within minutes of TNF stimulation (Hao and Baltimore 2009;Bhatt et al 2012;Schmidt et al 2015). In order to track these changes, we isolated and sequenced total-cell RNA collected at 0, 30, 60, and 90 min post-stimulation.…”

Models of human core transcriptional regulatory circuitries

“…Another consideration is the challenge of comprehensive experimental validation of the circuits, which would in principle require knock-out of individual core TFs and perhaps combinations of these TFs. Ongoing efforts to characterize DNA-binding motifs for TFs Mathelier et al 2014;Hume et al 2015), taking into account the influence of their TF partners, and the role of coactivators and chromatin regulators on their binding to regulatory sequences (Chen et al 2008;Yan et al 2013;Siersbaek et al 2014a;Schmidt et al 2015), and further experimental testing should help refine the description of the CRC models we provide here.…”

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

“…Recently, clusters of putative enhancers (named 'super-enhancers') have been shown to regulate the expression of genes defining cell identity (Whyte et al, 2013). They have also been found to be deregulated in diseases such as cancer and inflammation (Brown et al, 2014;Chapuy et al, 2013;Hnisz et al, 2013;Mansour et al, 2014;Schmidt et al, 2015;Vahedi et al, 2015), but have not yet been studied in context of UV exposure.…”