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FIRST LOOK: Harnessing Endogenous Mechanisms of Programmed Gene Expression for Therapeutic Benefit in Cardiometabolic Disorders

Proximal mechanisms for programmatic control of gene expression exist that underlie the complex, distinct and at times disparate components of cardiometabolic health and dysfunction. Identifying such pathways offers new insights into physiologic and pathologic states, novel treatment strategies and a more rational basis for therapies based on endogenous biology. Through this focus, we identified how modulating key nuclear receptors limits inflammation or decreases visceral obesity, under pursuit as novel therapies.

Epigenetics offers a completely distinct way to control complex transcriptional programs via histone modifications. While most efforts have focused on the placing (‘writers’, e.g. HATs) or removal (‘erasers’, e.g. HDACs) of histone marks, less attention has been directed to epigenetic proteins that bind to these marks (‘readers’) and allow transcription to proceed. The bromodomain and extra-terminal (BET)-containing family, including BRD2, BRD3 and BRD4, which bind to acetylated histones, are epigenetic reader proteins strongly implicated as therapeutic targets in cancer but previously unexplored in cardiovascular and metabolic disorders. In endothelial cells (ECs), we found BRD4 to be essential in transducing the inflammatory NF-kappa B signal to chromatin. In response to TNFα, endothelial BRD4 undergoes massive redeployment to a defined set of de novo super enhancers that drives the resulting pro-inflammatory, pro-atherosclerotic program, as seen in global ChIP-Seq studies. In vivo, BET inhibition decreases inflammation and atherosclerosis.

Of note, TNFα stimulation decommissions BRD4 already active in running an endothelial gene expression program under basal conditions. BET modulation offers several novel therapeutic approaches. Selective BET inhibition, via distinct chemical structures and drug delivery, allows for potent disruption of a coordinated program involved in the pathogenesis of specific diseases while BET biology provides unique targets for manipulation. Separately, BET localization across the genome provides a new way of identifying previously unrecognized players in the inflammation and atherosclerosis as well as the maintenance of normal endothelial function. Such efforts are further supported by additional work extending BET action to other vascular and metabolic settings.

 

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