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Modulating the Genomic Programming of Adipocytes.

The ability to modify the transcriptional program in response to external signals provides a way for mammalian cells to alter their biological fate and properties, thereby adapting to changes in the environment. Adipocytes are excellent examples of differentiated cells that possess a striking transcriptional plasticity when exposed to physiological and metabolic stimuli. In our work, we have focused on understanding the processes responsible for modulating the genomic programming in response to different external signals. Thus, we have shown that browning of human adipocytes with rosiglitazone, an antidiabetic agonist of the key adipocyte transcription factor peroxisome proliferator-activated receptor γ (PPARγ), involves redistribution of PPARγ binding to form browning-selective PPARγ super-enhancers that drive expression of key browning genes. These include genes encoding transcriptional regulators, such as Krüppel-like factor 11 (KLF11) that are essential for modulating the genomic program in white adipocytes to induce browning. Furthermore, we have shown that acute suppression of adipocyte genes by the proinflammatory cytokine, tumor necrosis factor (TNF), involves redistribution of cofactors to enhancers activated by the master inflammatory regulator, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Interestingly, this redistribution occurs selectively from enhancers with high-cofactor occupancies, thereby predominantly affecting super-enhancers and their associated genes. We propose that this is a general mechanism contributing to transcriptional repression associated with activation of signal-dependent transcription factors.