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A transcriptional switch governs fibroblast activation in heart disease
Open accessPublished version of a preprint
Abstract
In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear 1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction 3-7, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.
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“As expected4, fibroblasts had the highest enrichment of genes whose expression significantly correlated with cardiac function (Fig. 1E).”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“The possibility that JQ1 treatment can reversibly direct fibroblast activation away from the FAP/POSTN cell state indicates the therapeutic potential of targeting the differentiation and maturation of FAP+ fibroblasts28,30.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [28]
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“BET inhibition exerted a strong protective effect on left ventricular ejection fraction (Fig. 1B)4,6-10.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“We previously showed the specific importance of BRD4 in aspects of heart failure pathogenesis4,25.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“Given our observation that transcriptional changes associated with JQ1 in the cardiomyocyte (CM) compartment are modest compared to other cardiac cell populations4,11”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“RNA-seq and DE analysis among fibroblasts identified a small group of genes that were sensitive to TGFB stimulation and had increased expression when TGFB and IL1B were used in combination (Fig. 5B). These included genes such as SERPINA9, EGR2, LRRC152 and MEOX1, a critical transcriptional regulator of cardiac fibroblast activation.4.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“Motif analysis of these regions revealed enrichment for TFs critical for profibrotic responses in heart failure, such as SMADs27 and MEOX14, as well as RUNX1 and REL, regulators of proinflammatory responses27 (Extended Data Fig. 4D).”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“We previously demonstrated that pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins, critical mediators of stress-activated chromatin signaling in various diseases3, modulates a reversible transcriptional switch that governs fibroblast activation in chronic heart failure through the transcription factor (TF) MEOX14.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“As our previous work demonstrated that Meox1 transcription is sensitive to BET inhibition4, which we confirmed in human cardiac fibroblasts treated with IL1B and TGFB (Extended Data Fig. 9Q)”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“We found reductions in chromatin accessibility at the Postn and Meox1 loci in TAC-Brd4KO fibroblasts, including regulatory elements we previously showed were essential for stress-induced activation of those genes (Fig. 3Q, regions highlighted in red)4.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“Within the human MEOX1 locus, we found that the region associated with strong enrichment of H3K27Ac was the syntenic element of the mouse stress-dependent Meox1 Peak9/10 enhancer4 (Fig. 5D).”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“a critical regulator of the stress-activated fibroblast response4”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [4]
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“MEOX1 was previously implicated in cardiac fibrosis28.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [28]
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“Indeed, previous and concurrent work has highlighted the functional role of this gene regulatory network in cardiac fibrosis28–30.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [28]
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Metadata
- Authors
- Alexanian, M., Przytycki, P. F., Micheletti, R., Padmanabhan, A., Ye, L., Travers, J. G., Gonzalez-Teran, B., Silva, A. C., Duan, Q., Ranade, S. S., Felix, F., Linares-Saldana, R., Li, L., Lee, C. Y., Sadagopan, N., Pelonero, A., Huang, Y., Andreoletti, G., Jain, R., McKinsey, T. A., Rosenfeld, M. G., Gifford, C. A., Pollard, K. S., Haldar, S. M., & Srivastava, D.
- Affiliations
- Gladstone Institutes (US)
- Howard Hughes Medical Institute (US)
- University of Colorado Anschutz (US)
- University of Pennsylvania (US)
- University of California, San Francisco (US)
- Amgen (United States) (US)
- Corresponding author
- Haldar, Saptarsi M.
- Srivastava, Deepak
- ORCID
- Alexanian, Michael
- Przytycki, Pawel F.
- Micheletti, Rudi
- Padmanabhan, Arun
- Travers, Joshua G.
- Gonzalez-Teran, Barbara
- Silva, Ana Catarina
- Duan, Qiming
- Ranade, Sanjeev S.
- Felix, Franco
- Linares-Saldana, Ricardo
- Li, Li
- Lee, Clara Youngna
- Pelonero, Angelo
- Huang, Yu
- Andreoletti, Gaia
- Jain, Rajan
- McKinsey, Timothy A.
- Gifford, Casey A.
- Pollard, Katherine S.
- Haldar, Saptarsi M.
- Srivastava, Deepak
- Venue
- Nature
- Published
- 2021-06-23
- Volume
- 595
- Issue
- 7867
- Pages
- 438-443
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8341289
- OpenAlex
- W3176137376
- Cited by
- 238
- References
- 53
- Citations by year
- 2026: 43 · 2025: 48 · 2024: 47 · 2023: 39 · 2022: 45 · 2021: 13
- FWCI
- 24.11
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- American Heart Association (18POST34080175, 16SFRN31400013)
- A.P. Giannini Foundation (P0527061)
- Tobacco-Related Disease Research Program (578649)
- Gladstone Institutes
- Giannini Foundation of Agricultural Economics (P0527061)
- Roddenberry Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186704)
- National Institutes of Health (16SFRN31400013, P01 HL098707, 1c06rr018928-01, HL146366, HL098179)
- Agency for Healthcare Research and Quality (R01HS015100)
- National Heart, Lung, and Blood Institute (F32HL147463, R01HL147558, R01HL116848, R01HL139783, P01HL146366, UM1HL098179, R01HL150100, P01HL089707, R01HL127240, R01HL150521, U01HL098179, R01HL150225, R01HL057181, K08HL157700)
- National Institute of Mental Health (R01MH123178)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119594)
- National Center for Research Resources (C06-RR-018928, RR018928)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- fibroblast activation, cardiac fibroblasts, BET proteins, MEOX1, transcriptional switch, chromatin accessibility, enhancers, TGF-beta signaling, myocardial fibrosis, cardiac dysfunction, fibrotic diseases, BET inhibitors, cis-regulatory elements, single-cell epigenomics
- MeSH terms
- Bromodomain Containing Proteins, Animals, Chromatin, Enhancer Elements, Genetic, Fibroblasts, Gene Expression Regulation, Heart Diseases, Humans, Proteins, Transcription Factors, Transforming Growth Factor beta, Homeodomain Proteins, Mice, Epigenomics, Single-Cell Analysis, Transcriptome
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