BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

Duan, Qiming; McMahon, Sarah; Anand, Priti; Shah, Hirsh; Thomas, Sean; Salunga, Hazel T.; Huang, Yu; Zhang, Rongli; Sahadevan, Aarathi; Lemieux, Madeleine E.; Brown, J.; Srivastava, Deepak; Bradner, James E.; McKinsey, Timothy A.; Haldar, Saptarsi M.

doi:10.1126/scitranslmed.aah5084

Cited by 217 publications

(236 citation statements)

References 71 publications

(172 reference statements)

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“…Also, it acts as an important regulator in multiple cellular processes, and its inhibitor (JQ1) draws much attention for therapeutic effects against tumor growth (17). Emerging studies have shown a close association between chronic inflammation and diabetes (18), whereas it has been recently discovered that BRD4 regulates inflammation (19,20). Thus, we assume that BRD4 may be involved in diabetic IVDD, especially MMP-13 expression in NPCs.…”

mentioning

confidence: 93%

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Wang

Chen³

et al. 2019

FASEB j.

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Diabetes mellitus may lead to intervertebral disc degeneration (IVDD). Matrix metalloproteinase‐13 (MMP‐13) is one of the major catabolic factors in extracellular matrix (ECM) metabolism of nucleus pulposus cells (NPCs) and contributes to diabetic IVDD. Bromodomain‐containing protein 4 (BRD4) is a member of the bromodomain and extraterminal protein family and is implicated in chronic inflammation. Here, we report that the expression of BRD4 and MMP‐13 was elevated in diabetic nucleus pulposus tissues as well as in advanced glycation end products (AGEs)‐treated NPCs; also, the regulatory effect of BRD4 on MMP‐13 was studied. We found that MMP‐13 was regulated by MAPK and NF‐κB signaling as well as autophagy in AGEs‐treated NPCs. Next, we explored the role of BRD4 in regulation of MAPK, NF‐κB signaling, and autophagy. The results showed that BRD4 is the upstream regulator of all of these 3 factors, and inhibition of BRD4 may suppress MAPK and NF‐κB signaling while activating autophagy in AGEs‐treated NPCs. Finally, we demonstrated that BRD4 inhibition may suppress MMP‐13 expression in diabetic NPCs in vitro as well as in vivo; meanwhile, it may preserve ECM in diabetic rats. Our study demonstrates that inhibition of BRD4 may suppress MAPK and NF‐κB signaling and activate autophagy to suppress MMP‐13 expression in diabetic IVDD, and diabetic IVDD may be compromised by BRD4 inhibitors.—Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., Gu, M., Wu, Y., Tian, N., Gao, W., Zhou, Y., Wang, X., Zhang, X. BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration. FASEB J. 33, 11555–11566 (2019). http://www.fasebj.org

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mentioning

confidence: 93%

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Wang

Chen³

et al. 2019

FASEB j.

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“…Some of these studies showed that the inhibitors disrupt BRD4bound SEs, resulting in oncogene downregulation (Lovén et al, 2013;Pelish et al, 2015;Bhagwat Anand et al, 2016). These drugs also inhibit inflammation and ameliorate related diseases, including LPSinduced sepsis, EAE-based neuroinflammation, diabetes, and cardiovascular diseases (Nicodeme et al, 2010;Bandukwala et al, 2012;Anand et al, 2013;Belkina et al, 2013;Mele et al, 2013;Brown Jonathan et al, 2014;Fu et al, 2014;Duan et al, 2017). These drugs also inhibit inflammation and ameliorate related diseases, including LPSinduced sepsis, EAE-based neuroinflammation, diabetes, and cardiovascular diseases (Nicodeme et al, 2010;Bandukwala et al, 2012;Anand et al, 2013;Belkina et al, 2013;Mele et al, 2013;Brown Jonathan et al, 2014;Fu et al, 2014;Duan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…These findings offered a possible mechanism of inhibitor action. These drugs also inhibit inflammation and ameliorate related diseases, including LPSinduced sepsis, EAE-based neuroinflammation, diabetes, and cardiovascular diseases (Nicodeme et al, 2010;Bandukwala et al, 2012;Anand et al, 2013;Belkina et al, 2013;Mele et al, 2013;Brown Jonathan et al, 2014;Fu et al, 2014;Duan et al, 2017). With these encouraging effects, BET inhibitors offer new therapeutic possibilities, mainly for blood cancers and inflammation (Belkina & Denis, 2012;Ceribelli et al, 2014;Berthon et al, 2016;Ghosh et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

et al. 2019

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BRD4 is a BET family protein that binds acetylated histones and regulates transcription. BET/BRD4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout (KO) mice showed that BRD4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4 played limited roles in macrophage development and inflammatory response to LPS. ChIP‐seq analysis showed that despite its limited importance, BRD4 broadly occupied the macrophage genome and participated in super‐enhancer (SE) formation. Although BRD4 is critical for SE formation in cancer, BRD4 was not required for macrophage SEs, as KO macrophages created alternate, BRD4‐less SEs that compensated BRD4 loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context‐dependent role of BRD4 and plasticity of epigenetic regulation.

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“…We aimed to assess whether TRIAGE could identify transcriptional signatures of therapeutic interventions in heart failure (HF). Previous studies have shown that the epigenetic reader protein BRD4, a member of the BET (Bromodomain and Extra Terminal) family of acetyl-lysine reader proteins, functions as a critical chromatin co-activator during HF pathogenesis that can be pharmacologically targeted in vivo (Anand et al, 2013;Duan et al, 2017;Spiltoir et al, 2013) to prevent and treat HF by targeting gene programs linked to cardiac hypertrophy and fibrosis (Duan et al, 2017). We analyzed RNA-seq data from adult mouse hearts where pre-established HF (transverse aortic constriction, TAC) was treated with JQ1.…”

Section: Determining the Regulatory Control Points Of Diseasementioning

confidence: 99%

Conserved epigenetic regulatory logic infers genes governing cell identity

Shim

Sinniah

et al. 2019

Preprint

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Understanding genetic control of cell diversification is essential for establishing mechanisms controlling biological complexity. This study demonstrates that the a priori deposition of H3K27me3 associated with gene repression across diverse cell states provides a genome-wide metric that enriches for genes governing fundamental mechanisms underlying biological complexity in differentiation, morphogenesis, and disease. We use this metric in combination with more than 1 million genome-wide data sets from diverse omics platforms to identify cell type specific regulatory mechanisms underlying diverse organ systems from species across the animal kingdom. From this analysis, we identify and genetically validate multiple novel genes controlling heart development in diverse chordates including humans and the tunicate, Ciona robusta. This study demonstrates that the conservation of epigenetic regulatory logic provides an effective strategy for utilizing large, diverse genome-wide data to establish quantitative basic principles of cell states to infer cell-type specific mechanisms that underpin the complexity of biological systems. AUTHOR CONTRIBUTIONS WJS:Developed the computational basis for the study, performed data analysis and wrote the manuscript. ES: Assisted in experimental and computational design for the study, performed data analysis, carried out functional genetic studies in hPSCs and wrote the manuscript. JX: Assisted with computational analysis and developed web interactive interface. MA: Performed computational analysis on HF pathogenesis data GA: Performed computational analysis on HF pathogenesis data SS: Assisted the computational analysis on different single-cell data platforms. BB: Performed computational analysis on melanoma studies. YS: Performed computational analysis on Mouse Organogenesis Cell Atlas data. BV: Performed functional analysis on ciona and validated the findings GP: Assisted with spatiotemporal transcriptomic profiling of mouse gastrulation NJ: Assisted with spatiotemporal transcriptomic profiling of mouse gastrulation YW: Helped with computational analysis of epigenetic data MP: Assisted with analysis and interpretation of melanoma data AS: Carried out experiments involving melanoma analysis YC: Carried out experiments involving melanoma analysis PT: Supervised work on spatiotemporal transcriptomic profiling of mouse gastrulation LC: Performed functional analysis on ciona and validated the findings DS: Supervised work on analysis of HF pathogenesis data QN: Provided assistance to implement TRIAGE on single-cell data sets. MB and NJP: Supervised the project, raised funding, and wrote the manuscript.

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BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

Cited by 217 publications

References 71 publications

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

Conserved epigenetic regulatory logic infers genes governing cell identity

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