Transcription Factor Cooperativity in Early Adipogenic Hotspots and Super-Enhancers

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

“…It is possible that LPS maximizes inflammatory responses by redistributing TFs that are required to transcribe genes involved in normal cellular metabolism in a resting condition to SEs that mark functionally relevant proinflammatory genes. Thus, the decrease in transcriptional levels might be due to either a loss or redistribution of these TFs or, as previously shown in other systems, a sequestering of TFs (14,29,30,33). Further studies are needed to address this issue.…”

“…Nearly 27% of transcripts were classified as eRNAs, found in intergenic regions, closely associated with TFs and epigenetic modifications. We observed that eRNAs were typically clustered at key genes within enhancer-dense regions, resembling sites that were recently described as SEs (12)(13)(14). To explore the relationship between eRNAs and SEs more closely, we analyzed ChIP-Seq data for key macrophage TFs, PU.1, C/EBPA, JUNB, and NF-κB p65 (RELA), and defined SEs based on the binding of these key factors (Dataset S1).…”

“…However, most studies focused mainly on the functions of enhancers and eRNAs in transcriptional activation, whereas signal-dependent transcriptional repression has not been directly addressed in the context of enhancer function. Recent studies have demonstrated that signaling through nuclear receptors such as ER and peroxisome proliferator-activated receptor can cause release of coactivators at enhancers, resulting in repression of gene expression (14,29,30). However, the contribution of eRNA repression, if any, to this process remains unknown.…”

“…Recent studies exploring how enhancers exert their functions in gene regulation have revealed a variety of enhancer properties including chromatin looping between enhancers and target gene promoters, enhancer-specific histone modification such as histone H3 mono-and di-methyl lysine 4 and H3 lysine 27 acetylation modifications, histone variants, coactivator binding, and an open chromatin architecture (3,(5)(6)(7)(8)(9)(10)(11). More recent studies have indicated that enhancers are the key elements in cell-type specificity and have shown that there are regions where enhancers are clustered together near key genes that are involved in determining cell identity, called "super enhancers" (SEs) or "stretch enhancers" (12)(13)(14)(15). It has been shown that these enhancer-dense regions are distinct from the typical enhancers (TEs) in their ability to activate cell-type and tissue-specific genes and result in a higher susceptibility for disease when mutated (12,13,15,16).…”

Toward Integrative Annotation of Cell Type-Specific Epigenomes to Better Understand Human Biology and Disease

“…TFs bind to genomic sequences known as hotspots through mediated by combinations of core and stage-specific factors and other chromatin-associated proteins [3,4]. In the early phase of adipogenesis, approximately 12,000 hotspots can recruit TFs both simultaneously and sequentially to facilitate lineage commitment.…”