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Epigenetic reader BRD4 (Bromodomain-Containing Protein 4) governs nucleus-encoded mitochondrial transcriptome to regulate cardiac function

Item Type:Article
Title:Epigenetic reader BRD4 (Bromodomain-Containing Protein 4) governs nucleus-encoded mitochondrial transcriptome to regulate cardiac function
Creators Name:Kim, S.Y. and Zhang, X. and Schiattarella, G.G. and Altamirano, F. and Ramos, T.A.R. and French, K.M. and Jiang, N. and Szweda, P.A. and Evers, B.M. and May, H.I. and Luo, X. and Li, H. and Szweda, L.I. and Maracaja-Coutinho, V. and Lavandero, S. and Gillette, T.G. and Hill, J.A.
Abstract:BACKGROUND: BET (Bromodomain and Extra-Terminal) epigenetic reader proteins, in particular BRD4, have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecule BET protein inhibitors, such as JQ1, have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BET proteins in the heart have not been conducted to validate pharmacological findings and unveil potential pharmacological side effects. METHODS: By engineering a cardiomyocyte-specific BRD4 (bromodomain-containing protein 4) knockout mouse, we investigated the role of BRD4 in cardiac pathophysiology. We performed functional, transcriptomic, and mitochondrial analysis to evaluate BRD4 function in developing and mature hearts. RESULTS: Unlike pharmacological inhibition, loss of BRD4 protein triggered progressive declines in myocardial function, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse heart tissue identified early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria from these hearts confirmed that BRD4 ablation triggered significant changes in mitochondrial electron transport chain protein expression and activity. Computational analysis identified candidate transcription factors participating in the BRD4-regulated transcriptome. In particular, ESRRα (estrogen-related receptor alpha), a key nuclear receptor in metabolic gene regulation, was enriched in promoters of BRD4-regulated mitochondrial genes. CONCLUSIONS: In aggregate, we describe a previously unrecognized role for BRD4 in regulating cardiomyocyte mitochondrial homeostasis, observing that its function is indispensable to the maintenance of normal cardiac function.
Keywords:Human BRD4 Protein, Electron Transport, Epigenetics, Heart Failure, Mitochondria, Genetic transcription, Animals, Mice
Source:Circulation
ISSN:0009-7322
Publisher:American Heart Association
Volume:142
Number:24
Page Range:2356-2370
Date:15 December 2020
Additional Information:Copyright © 2020 American Heart Association, Inc.
Official Publication:https://doi.org/10.1161/CIRCULATIONAHA.120.047239
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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