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A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease

Michael Alexanian, Pawel F. Przytycki, Rudi Micheletti, Arun Padmanabhan, Lin Ye, Joshua G. Travers, Barbara Gonzalez Teran, Qiming Duan, Sanjeev S. Ranade, Franco Felix, Ricardo Linares-Saldana, Yu Huang, Gaia Andreoletti, Jin Yang, Kathryn N. Ivey, Rajan Jain, Timothy A. McKinsey, Michael G. Rosenfeld, Casey Gifford, Katherine S. Pollard, Saptarsi M. Haldar, Deepak Srivastava
doi: https://doi.org/10.1101/2020.07.21.214874
Michael Alexanian
1Gladstone Institutes, San Francisco, CA, United States of America
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Pawel F. Przytycki
1Gladstone Institutes, San Francisco, CA, United States of America
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Rudi Micheletti
2Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093
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Arun Padmanabhan
1Gladstone Institutes, San Francisco, CA, United States of America
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Lin Ye
1Gladstone Institutes, San Francisco, CA, United States of America
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Joshua G. Travers
3Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Barbara Gonzalez Teran
1Gladstone Institutes, San Francisco, CA, United States of America
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Qiming Duan
1Gladstone Institutes, San Francisco, CA, United States of America
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Sanjeev S. Ranade
1Gladstone Institutes, San Francisco, CA, United States of America
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Franco Felix
1Gladstone Institutes, San Francisco, CA, United States of America
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Ricardo Linares-Saldana
4Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Yu Huang
1Gladstone Institutes, San Francisco, CA, United States of America
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Gaia Andreoletti
5Institute for Computational Health Sciences, University of California, San Francisco, CA 94158, USA
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Jin Yang
6Tenaya Therapeutics, 171 Oyster Point Blvd suite 500, South San Francisco, CA 94080
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Kathryn N. Ivey
6Tenaya Therapeutics, 171 Oyster Point Blvd suite 500, South San Francisco, CA 94080
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Rajan Jain
4Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Timothy A. McKinsey
3Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Michael G. Rosenfeld
2Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093
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Casey Gifford
1Gladstone Institutes, San Francisco, CA, United States of America
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Katherine S. Pollard
1Gladstone Institutes, San Francisco, CA, United States of America
7Chan-Zuckerberg Biohub, San Francisco, CA, USA
8Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California, San Francisco, CA, USA; Department of Medicine, Cardiology Division, UCSF School of Medicine, San Francisco, CA, USA
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Saptarsi M. Haldar
1Gladstone Institutes, San Francisco, CA, United States of America
8Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California, San Francisco, CA, USA; Department of Medicine, Cardiology Division, UCSF School of Medicine, San Francisco, CA, USA
12Amgen Research, Cardiometabolic Disorders, South San Francisco, California, USA
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  • For correspondence: deepak.srivastava@gladstone.ucsf.edu saptarsi.haldar@gladstone.ucsf.edu
Deepak Srivastava
1Gladstone Institutes, San Francisco, CA, United States of America
9Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA
10Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA
11Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
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  • For correspondence: deepak.srivastava@gladstone.ucsf.edu saptarsi.haldar@gladstone.ucsf.edu
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Abstract

In diseased organs, stress-activated signaling cascades alter chromatin, triggering broad shifts in transcription and cell state that exacerbate pathology. Fibroblast activation is a common stress response that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains poorly understood1,2. Pharmacologic inhibition of the BET family of transcriptional coactivators alleviates cardiac dysfunction and associated fibrosis, providing a tool to mechanistically interrogate maladaptive fibroblast states and modulate their plasticity as a potential therapeutic approach3–8. Here, we leverage dynamic single cell transcriptomic and epigenomic interrogation of heart tissue with and without BET inhibition to reveal a reversible transcriptional switch underlying stress-induced fibroblast activation. Transcriptomes of resident cardiac fibroblasts demonstrated robust and rapid toggling between the quiescent fibroblast and activated myofibroblast state in a manner that directly correlated with BET inhibitor exposure and cardiac function. Correlation of single cell chromatin accessibility with cardiac function revealed a novel set of reversibly accessible DNA elements that correlated with disease severity. Among the most dynamic elements was an enhancer regulating the transcription factor MEOX1, which was specifically expressed in activated myofibroblasts, occupied putative regulatory elements of a broad fibrotic gene program, and was required for TGFβ-induced myofibroblast activation. CRISPR interference of the most dynamic cis-element within the enhancer, marked by nascent transcription, prevented TGFβ-induced activation of Meox1. These findings identify MEOX1 as a central regulator of stress-induced myofibroblast activation associated with cardiac dysfunction. The plasticity and specificity of the BET-dependent regulation of MEOX1 in endogenous tissue fibroblasts provides new trans- and cis- targets for treating fibrotic disease.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease
Michael Alexanian, Pawel F. Przytycki, Rudi Micheletti, Arun Padmanabhan, Lin Ye, Joshua G. Travers, Barbara Gonzalez Teran, Qiming Duan, Sanjeev S. Ranade, Franco Felix, Ricardo Linares-Saldana, Yu Huang, Gaia Andreoletti, Jin Yang, Kathryn N. Ivey, Rajan Jain, Timothy A. McKinsey, Michael G. Rosenfeld, Casey Gifford, Katherine S. Pollard, Saptarsi M. Haldar, Deepak Srivastava
bioRxiv 2020.07.21.214874; doi: https://doi.org/10.1101/2020.07.21.214874
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A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease
Michael Alexanian, Pawel F. Przytycki, Rudi Micheletti, Arun Padmanabhan, Lin Ye, Joshua G. Travers, Barbara Gonzalez Teran, Qiming Duan, Sanjeev S. Ranade, Franco Felix, Ricardo Linares-Saldana, Yu Huang, Gaia Andreoletti, Jin Yang, Kathryn N. Ivey, Rajan Jain, Timothy A. McKinsey, Michael G. Rosenfeld, Casey Gifford, Katherine S. Pollard, Saptarsi M. Haldar, Deepak Srivastava
bioRxiv 2020.07.21.214874; doi: https://doi.org/10.1101/2020.07.21.214874

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