Drugging transcription in heart failure

Abstract

Pathological Stress Improved Function Present Future THERAPY ERK Pathogenic Gene mRNA Cytoplasm Nucleus JQ1 ExtracellularAbstract Advances in our understanding of the basic biology and biochemistry of chromatin structure and function at genome scales has led to tremendous growth in the fields of epigenomics and transcriptional biology. While it has long been appreciated that transcriptional pathways are dysregulated in failing hearts, only recently has the idea of disrupting altered transcription by Arun Padmanabhan is a physician-scientist at the University of California, San Francisco and a postdoctoral scholar at the Gladstone Institutes. His research focuses on understanding the gene-regulatory and epigenetic pathways that govern cell fate decisions during early cardiac development and cell state transitions in the pathophysiology of heart failure. Saptarsi Haldar is a physician-scientist who is currently Vice President of Research at Amgen where he heads Cardiovascular and Metabolic Discovery, based in South San Francisco. He is also a Professor of Medicine at the University of California, San Francisco (visiting clinical appointment) and a Visiting Investigator at the Gladstone Institutes. His academic laboratories' research focuses on gene regulatory signalling mechanisms that govern cardiovascular and metabolic homeostasis. Abstract figure legendStress-or injury-induced cardiac signalling cascades converge on the nucleus to trigger global shifts in gene expression that contribute to the cycle of adverse remodelling and impaired function of the heart. Current pharmacological therapies target a very proximal step in stress-dependent cardiac signalling (e.g. antagonists of the β1 adrenergic receptor). As transcription factors and the chromatin regulatory apparatus act as the terminal signal integrators that transduce these signals into changes in cell identity, disrupting altered transcription by targeting chromatin-associated proteins has emerged as an exciting potential therapeutic avenue.

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

“…A number of transcription factor modulators are currently in preclinical and clinical development for other diseases, namely cancer, 77 and transcription factors have also been explored as therapeutic targets for certain cardiovascular diseases, such as heart failure. 78 As such, therapeutic modulation of key transcriptional machinery involved in vascular cell state shifts may represent a fruitful avenue for further investigation.…”

Emerging roles of BET proteins in transcription and co‐transcriptional RNA processing

“…Bromodomain and extraterminal (BET) proteins play roles in fundamental cellular processes including transcription, chromatin organization, cell cycle control, DNA repair, DNA replication, and RNA processing (Arnold et al, 2021; Dey et al, 2009; Edwards et al, 2020; S. C. Hsu & Blobel, 2017; Kim et al, 2019; Lam et al, 2020; Uppal et al, 2019; Wu & Chiang, 2007), and have been implicated in a range of human diseases (Jacques et al, 2020; Morgado‐Pascual et al, 2019; Padmanabhan & Haldar, 2020; Shi & Vakoc, 2014; C.‐Y. Wang & Filippakopoulos, 2015).…”

BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

“…This stress-coupled activation of DNA binding proteins in HF elicits global changes in chromatin structure and post-translational modifications on histone proteins, including lysine acetylation of histone tails, TFs, and other chromatin associated proteins. Given the central role of signal-coupled gene transcription in cardiac plasticity, manipulation of chromatin-dependent signaling as a therapeutic approach for HF has been an area of intense interest 7,8 .…”