The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“MEOX1 was previously implicated in cardiac fibrosis28.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
Liao, Y., Smyth, G. K., & Shi, W. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt656 · Cited by 27,219
Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association
Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000757 · Cited by 9,175
Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool
Chen, E. Y., Tan, C. M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G. V., Clark, N. R., & Ma’ayan, A. (2013) · BMC Bioinformatics · doi:10.1186/1471-2105-14-128 · Cited by 7,814
Self-citationDimensionality reduction for visualizing single-cell data using UMAP
Becht, E., McInnes, L., Healy, J., Dutertre, C.-A., Kwok, I. W. H., Ng, L. G., Ginhoux, F., & Newell, E. W. (2019) · Nature Biotechnology · doi:10.1038/nbt.4314 · Cited by 5,358
Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143
CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes
Gilbert, L. A., Larson, M. H., Morsut, L., Liu, Z., Brar, G. A., Torres, S. E., Stern-Ginossar, N., Brandman, O., Whitehead, E. H., Doudna, J. A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.044 · Cited by 3,696
Cited by
Sorted by citations
Spatial multi-omic map of human myocardial infarction
Kuppe, C., Ramirez Flores, R. O., Li, Z., Hayat, S., Levinson, R. T., Liao, X., Hannani, M. T., Tanevski, J., Wünnemann, F., Nagai, J. S., et al. (2022) · Nature · doi:10.1038/s41586-022-05060-x · Cited by 772
Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure
Koenig, A. L., Shchukina, I., Amrute, J., Andhey, P. S., Zaitsev, K., Lai, L., Bajpai, G., Bredemeyer, A., Smith, G., Jones, C., et al. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00028-6 · Cited by 482
Targeting immune–fibroblast cell communication in heart failure
Amrute, J. M., Luo, X., Penna, V., Yang, S., Yamawaki, T., Hayat, S., Bredemeyer, A., Jung, I.-H., Kadyrov, F. F., Heo, G. S., et al. (2024) · Nature · doi:10.1038/s41586-024-08008-5 · Cited by 339
Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction
Janbandhu, V. C., Tallapragada, V. J., Patrick, R., Li, Y., Abeygunawardena, D., Humphreys, D. T., Martin, E. M. M. A., Ward, A. O., Contreras, O., Farbehi, N., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.10.009 · Cited by 230
Therapeutic targets for cardiac fibrosis: from old school to next-gen
Travers, J. G., Tharp, C. A., Rubino, M., & McKinsey, T. A. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148554 · Cited by 179
Self-citation
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
