A transcriptional switch governs fibroblast activation in heart disease

Alexanian, Michael; Przytycki, Pawel F.; Micheletti, Rudi; Padmanabhan, Arun; Ye, Lin; Travers, Joshua G; González‐Terán, Bárbara; Silva, Ana Catarina; Duan, Qiming; Ranade, Sanjeev S.; Felix, Franco; Linares-Saldana, Ricardo; Li, Li; Lee, Clara Youngna; Sadagopan, Nandhini; Pelonero, Angelo; Huang, Yu; Andreoletti, Gaia; Jain, Rajan; McKinsey, Timothy A.; Rosenfeld, Michael G.; Gifford, Casey A.; Pollard, Katherine S.; Haldar, Saptarsi M.; Srivastava, Deepak

doi:10.1038/s41586-021-03674-1

Cited by 116 publications

(132 citation statements)

References 22 publications

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“…[108] BRD4 controls the fibrotic gene regulatory network and promotes the progression of fibrotic diseases. [109] High glucose upregulates BRD4 which in turn modulates KEAP1-NRF2 signaling pathway in podocytes F I G U R E 4 Three categories of BETis. A: Pan-BD inhibitor.…”

Section: The Contribution Of Brd4 To Other Non-cancerous Diseasesmentioning

confidence: 99%

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Liang

Tian

2021

BioEssays

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Bromodomain-containing 4 (BRD4), a member of Bromo and Extra-Terminal (BET) family, recognizes acetylated histones and is of importance in transcription, replication, and DNA repair. It also binds non-histone proteins, DNA and RNA, contributing to development, tissue growth, and various physiological processes. Additionally, BRD4 has been implicated in driving diverse diseases, ranging from cancer, viral infection, inflammation to neurological disorders. Inhibiting its functions with BET inhibitors (BETis) suppresses the progression of several types of cancer, creating an impetus for translating these chemicals to the clinic. The diverse roles of BRD4 are largely dependent on its interaction partners in different contexts. In this review we discuss the molecular mechanisms of BRD4 with its interacting partners in physiology and pathology. Current development of BETis is also summarized. Further understanding the functions of BRD4 and its partners will facilitate resolving the liabilities of present BETis and accelerate their clinical translation.

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Section: The Contribution Of Brd4 To Other Non-cancerous Diseasesmentioning

confidence: 99%

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Liang

Tian

2021

BioEssays

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“…In CFs, TGF-β signaling targets BRD4 binding to discrete SEs in a p38 kinase–dependent manner, providing a circuit for coupling extracellular cues to the cardiac epigenome to drive profibrotic gene expression ( 135 ). Subsequent studies, using single-cell technologies, identified distal regulatory elements in CFs that had increased chromatin accessibility after TAC that were closed upon JQ1 treatment ( 136 ). One of the most highly regulated elements was a large enhancer downstream of the gene encoding Meox1, a homeodomain-containing transcription factor whose expression was highly upregulated in myofibroblasts after TAC and suppressed by JQ1.…”

Section: Targeting Epigenetics As An Antifibrotic Therapeutic Approachmentioning

confidence: 99%

Therapeutic targets for cardiac fibrosis: from old school to next-gen

Travers¹,

Tharp²,

Rubino³

et al. 2022

Journal of Clinical Investigation

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Cardiovascular diseases remain the leading cause of death worldwide, with pathological fibrotic remodeling mediated by activated cardiac myofibroblasts representing a unifying theme across etiologies. Despite the profound contributions of myocardial fibrosis to cardiac dysfunction and heart failure, there currently exist limited clinical interventions that effectively target the cardiac fibroblast and its role in fibrotic tissue deposition. Exploration of novel strategies designed to mitigate or reverse myofibroblast activation and cardiac fibrosis will likely yield powerful therapeutic approaches for the treatment of multiple diseases of the heart, including heart failure with preserved or reduced ejection fraction, acute coronary syndrome, and cardiovascular disease linked to type 2 diabetes. In this Review, we provide an overview of classical regulators of cardiac fibrosis and highlight emerging, next-generation epigenetic regulatory targets that have the potential to revolutionize treatment of the expanding cardiovascular disease patient population.

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“…As a result, interfering with IL-11 gene expression or blocking the binding of IL-11 to receptors can effectively prevent and treat cardiac fibrosis, suggesting that IL-11 is an important therapeutic target. By combining scRNA-seq and scATAC-seq, Alexanian et al (2021) recently identified that bromodomain and extraterminal (BET)-dependent regulation of MEOX1, a fibroblast-specific enhancer, controls fibroblast activation during chronic heart failure. In light of this, they suggested new therapeutic approaches targeting MEOX1 expression be developed instead of systemic BET inhibitors that have broad effects to alleviate the pathogenesis of fibrotic diseases.…”

Section: Scrna-seq and Cardiovascular Diseasementioning

confidence: 99%

Applications of Single-Cell RNA Sequencing in Cardiovascular Research

Fan

Han

Liu

et al. 2022

Front. Cell Dev. Biol.

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In recent years, cardiovascular disease (CVD) continues to be the leading cause of global disease burden. Extensive efforts have been made across basic, translational, and clinical research domains to curb the CVD epidemic and improve the health of the population. The successful completion of the Human Genome Project catapulted sequencing technology into the mainstream and aroused the interests of clinicians and scientific researchers alike. Advances in single-cell RNA sequencing (scRNA-seq), which is based on the transcriptional phenotypes of individual cells, have enabled the investigation of cellular fate, heterogeneity, and cell–cell interactions, as well as cell lineage determination, at a single-cell resolution. In this review, we summarize recent findings on the embryological development of the cardiovascular system and the pathogenesis and treatment of cardiovascular disease, as revealed by scRNA-seq technology. In particular, we discuss how scRNA-seq can help identify potential targets for the treatment of cardiovascular diseases and conclude with future perspectives for scRNA-seq.

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A transcriptional switch governs fibroblast activation in heart disease

Cited by 116 publications

References 22 publications

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Therapeutic targets for cardiac fibrosis: from old school to next-gen

Applications of Single-Cell RNA Sequencing in Cardiovascular Research

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