The DOI matches its Crossref record; 56 of the 57 references it cites were found in a registry or an index; 42 of the 45 sources its claims cite were checked for support.
Chromatin remodelling drives immune cell–fibroblast communication in heart failure
Open accessAbstract
Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers2, the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1+ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling. Conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ mouse macrophages ameliorates heart failure and substantially reduces fibroblast activation.
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96 Own result · 13 Supported · 13 Own interpretation · 10 Partly supported · 8 Own method · 2 No basis given · 1 Couldn’t confirm · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Given our observation that transcriptional changes associated with JQ1 in the cardiomyocyte (CM) compartment are modest compared to other cardiac cell populations4,11”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
In “Transcriptional plasticity of fibroblasts” (page not provided), the paper says JQ1’s effects on the cardiomyocyte transcriptome were modest compared with its previously published whole-LV signature. The same section reports substantial JQ1-dependent transcriptional shifts in fibroblasts, endothelial cells, and myeloid cells, supporting the citing sentence’s comparison. (LLM, conf=0.91)
- Partly supportedcites [11] Padmanabhan, A. et al. BRD4 (bromodomain-containing protein 4) interacts with GATA4 (GATA binding protein 4) to govern mitochondrial homeostasis in adult cardiomyocytes. Circulation 142, 2338–2355 (2020). sourceExperimental — accuracy not yet measured
The Results section reports that JQ1-treated sham-operated mouse hearts showed no dramatic transcriptional changes. The Discussion suggests that JQ1’s dominant targets in heart failure may be non-cardiomyocytes, but the paper does not directly compare JQ1-associated transcriptional changes in cardiomyocytes with those in other cardiac cell populations. (LLM, conf=0.83)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Flow cytometry analyses of cardiac tissue at day 7 post-TAC, a time point associated with immune cell expansion23,24, revealed no significant changes in the number of infiltrated immune cells, monocytes, or macrophages following JQ1 (Extended Data Fig. 1H,I).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Supportedcites [23] Patel, B. et al. CCR2+ monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload. JACC Basic Transl. Sci. 3, 230–244 (2018). source
The citation is attached to the description of day 7 post-TAC as a time point associated with immune-cell expansion, not to the citing authors’ JQ1 result. In Results (Figure 1C), the source reports significantly more cardiac leukocytes and macrophages one week after TAC than after sham surgery. (LLM, conf=0.93)
- Supportedcites [24] Revelo, X. S. et al. Cardiac resident macrophages prevent fibrosis and stimulate angiogenesis. Circ. Res. 129, 1086–1101 (2021). source
The citations attach to the description of day 7 post-TAC as a time point associated with immune-cell expansion, not to the JQ1 result. The Results section, “Pressure overload-induced cardiac remodeling profoundly alters the cardiac immune cell composition,” reports increased cardiac immune cells one week after TAC. No page number is provided in our copy. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Clusters 1 and 5 had high expression of Ccr2, a marker of monocyte-derived macrophages that infiltrate from the circulation17-19 (Fig. 1J and Extended Data Fig. 1C-E).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Partly supportedcites [17] Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007). sourceExperimental — accuracy not yet measured
The Results section on chemokine-mediated recruitment (page unavailable) reports that circulating Ly-6Chi monocytes selectively express CCR2 and that their recruitment into infarcted myocardium depends on it. The paper distinguishes these monocytes from macrophages, however, and the cited passages do not establish CCR2 as a marker specifically of monocyte-derived macrophages. (LLM, conf=0.82)
- Supportedcites [18] Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014). source
The citation supports the marker interpretation, not the citing paper’s own measurement of clusters 1 and 5. In Results, under “CCR2 deficient mice distinguish local macrophage expansion from peripheral monocyte influx” (page unavailable), the source reports that CCR2-expressing blood monocytes are recruited into the heart and contribute to macrophage populations. (LLM, conf=0.91)
- Supportedcites [19] Bajpai, G. et al. Tissue resident CCR2− and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ. Res. 124, 263–278 (2019). source
The Results section (“Myocardial Injury Results in Shifts in Macrophage Ontogeny”) describes recruited CCR2+ monocytes and CCR2+ monocyte-derived macrophages after injury. The Results section on monocyte-derived macrophages further reports that most CCR2+ macrophages four days after injury were derived from recruited monocytes. The cited paper supports the marker interpretation; the cluster numbers are the citing paper’s own findings. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We previously showed the specific importance of BRD4 in aspects of heart failure pathogenesis4,25.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 function in Cx3cr1+ cells during heart failure
What the sources say
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
The Stress-induced cis-regulation of Meox1 section (page not provided) reports that stress-induced Meox1 activation in fibroblasts was most sensitive to BRD4 dosage among BET proteins. The paper connects this fibroblast-activation pathway to chronic heart failure pathogenesis, supporting the broad claim that BRD4 matters in an aspect of that process. (LLM, conf=0.90)
- Supportedcites [25] Stratton, M. S. et al. Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation. Circ. Res. 125, 662–677 (2019). source
The Discussion identifies BRD4 as a key pro-fibrotic factor that controls pathogenic gene expression in cardiac fibroblasts. It links that role to heart failure, supporting the claim about BRD4’s importance in an aspect of heart failure pathogenesis. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“As expected4, fibroblasts had the highest enrichment of genes whose expression significantly correlated with cardiac function (Fig. 1E).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Partly supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). sourceExperimental — accuracy not yet measured
The ‘Chromatin state and cardiac function’ section reports correlations between cardiac function and fibroblast enhancer accessibility, not gene expression. The ‘Transcriptional plasticity of fibroblasts’ section describes fibroblast transcriptomic changes, but our copy does not show that fibroblasts had the highest enrichment of genes whose expression significantly correlated with cardiac function. (LLM, conf=0.82)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“BET inhibition exerted a strong protective effect on left ventricular ejection fraction (Fig. 1B)4,6-10.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
The Transcriptional plasticity of fibroblasts section reports that JQ1 significantly improved left ventricular systolic function in mice after pressure-overload heart failure induced by transverse aortic constriction. The Chromatin state and cardiac function section identifies left ventricular ejection fraction as the measure of cardiac function across these treatment settings. Page numbers are unavailable in our copy. (LLM, conf=0.91)
- Supportedcites [6] Anand, P. et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 154, 569–582 (2013). source
In Results, under “BET Bromodomain inhibition arrests pathologic hypertrophy and heart failure in vivo” (page not provided), the paper identifies TAC as a mouse model of cardiac pressure overload and reports that JQ1 protected against TAC-mediated left ventricular systolic dysfunction on serial echocardiography. This supports the claim about protection of left ventricular ejection fraction, although the passage does not name that measure explicitly. (LLM, conf=0.89)
- Partly supportedcites [7] Spiltoir, J. I. et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J. Mol. Cell. Cardiol. 63, 175–179 (2013). sourceExperimental — accuracy not yet measured
The Results report that JQ1 rescued pressure-overload-induced left ventricular systolic dysfunction in mice subjected to transverse aortic constriction, as assessed by echocardiography. The available Results passage does not identify ejection fraction as the measure or quantify the strength of its protection, so those specifics are not verified. (LLM, conf=0.82)
- Supportedcites [8] Duan, Q. et al. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aah5084 (2017). source
The Results section on preestablished heart failure (page unavailable) reports that JQ1 attenuated left ventricular systolic dysfunction in mice with pressure-overload heart failure. The Methods section on echocardiography (page unavailable) identifies ejection fraction as a measured outcome. (LLM, conf=0.90)
- Partly supportedcites [9] Antolic, A. et al. BET bromodomain proteins regulate transcriptional reprogramming in genetic dilated cardiomyopathy. JCI Insight 5, e138687 (2020). sourceExperimental — accuracy not yet measured
The results report that JQ1 improved left-ventricular systolic function in PLN R9C mice with genetic dilated cardiomyopathy, as measured by fractional shortening. The Methods and results do not report ejection fraction or a pressure-overload heart-failure experiment in these mice; the Discussion mentions aortic banding only in connection with prior studies. Page numbers are unavailable in our copy. (LLM, conf=0.88)
- Partly supportedcites [10] Auguste, G. et al. BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C-deficient mice. J. Clin. Invest. 130, 4740–4758 (2020). sourceExperimental — accuracy not yet measured
The 'Effects of JQ1 on cardiac function' section reports improved left ventricular function after JQ1 treatment, but the mice had myocyte-specific lamin A/C deficiency, not pressure-overload heart failure. It reports improved fractional shortening (LVFS), not a measured protective effect on ejection fraction. The paper mentions beneficial effects in pressure-overload models only when discussing previous studies; page numbers are unavailable in our copy. (LLM, conf=0.87)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cx3cr1, which marks both monocyte-derived and resident macrophages20-22, was particularly enriched in cluster 1, together with proinflammatory genes such as Il1b (Fig. 1J).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Partly supportedcites [20] Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013). sourceExperimental — accuracy not yet measured
The Introduction describes CX3CR1 expression in monocytes, and Results > Dual origins of resident macrophages identifies CX3CR1-positive resident macrophages (no page number provided). These passages support the marker’s relevance to both populations, but do not establish that it marks monocyte-derived macrophages specifically. The cluster 1 and Il1b findings are attributed to the citing paper’s Figure 1J, not to this source. (LLM, conf=0.82)
- Partly supportedcites [21] Pinto, A. R. et al. An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLoS ONE 7, e36814 (2012). sourceExperimental — accuracy not yet measured
The Results section on the cTM gene-expression signature identifies Cx3cr1-GFP-positive cardiac tissue macrophages and says the GFP-positive splenic population includes monocytes and macrophages. It does not establish that Cx3cr1 marks both monocyte-derived and resident macrophages as distinct origins. The cluster 1 enrichment is attributed to the citing paper’s Fig. 1J, not to this source. (LLM, conf=0.82)
- Supportedcites [22] Lee, M., Lee, Y., Song, J., Lee, J. & Chang, S.-Y. Tissue-specific role of CX3CR1 expressing immune cells and their relationships with human disease. Immune Netw. 18, e5 (2018). source
The citation is attached to the statement that CX3CR1 marks both monocyte-derived and resident macrophages, not to the cluster 1 enrichment result. The Liver section describes CX3CR1 expression in macrophages derived from monocytes and in Kupffer cells, the liver’s specialized resident macrophages. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The Il1b distal region was among the most enriched genomic regions in p65/RELA binding (Fig. 4J and Extended Data Fig. 6B).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
What the sources say
- Could not verifycites [29] Link, V. M. et al. Analysis of genetically diverse macrophages reveals local and domain-wide mechanisms that control transcription factor binding and function. Cell 173, 1796–1809 (2018). sourceExperimental — accuracy not yet measured
The Results section on TF binding reports P65 ChIP-seq in BMDMs, but does not identify the Il1b distal region or rank its P65 binding against other genomic regions. Searches for Il1b, interleukin-1 beta, and the claimed enrichment found no passage addressing that comparison; page numbers were unavailable in our copy. (LLM, conf=0.74)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the 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.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
What the sources say
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
The cited paper’s ‘Enhancers during fibroblast activation’ section identifies Postn Peak10/11 as required for TGFβ-induced transactivation. Its ‘Stress-induced cis-regulation of Meox1’ section likewise identifies Meox1 Peak9/10 as required. The TAC-Brd4KO accessibility reductions are presented as the citing authors’ own finding; the citation supports their identification of the previously characterized regulatory elements. Page numbers were not provided in our copy. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the 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).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
What the sources say
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
The citation is attached to the mouse stress-dependent Meox1 Peak9/10 enhancer, not to the citing authors’ H3K27Ac finding in human iPSC-derived fibroblasts. In ‘Stress-induced cis-regulation of Meox1’ (page unavailable), the source identifies Peak9/10 as a stress-activated enhancer; ‘MEOX1 is upregulated in human fibrosis’ also identifies its syntenic region in humans. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- Probably not a substantial claim. 12
- It may state two separate claims as one. 42
Every source the paper cites for this claim was checked and supports it.
In the paper
“As BET proteins are transcriptional co-activators and their inhibition is associated with protection in heart failure models6-8”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Supportedcites [6] Anand, P. et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 154, 569–582 (2013). source
The Discussion describes BET proteins as transcriptional co-activators of pathologic gene expression in the heart. In the Results section, JQ1, a BET bromodomain inhibitor, protected mice against cardiac dysfunction and remodeling in a pressure-overload heart failure model. The copy provides no page numbers for these passages. (LLM, conf=0.94)
- Supportedcites [7] Spiltoir, J. I. et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J. Mol. Cell. Cardiol. 63, 175–179 (2013). source
The Discussion (section 4; page not provided) describes BET proteins as regulators that promote transcription during cardiac hypertrophy. The Abstract reports that the BET inhibitor JQ1 blocked left ventricular hypertrophy and improved cardiac function in mice subjected to pressure overload. The claim paraphrases these findings without asserting protection in patients with heart failure. (LLM, conf=0.88)
- Supportedcites [8] Duan, Q. et al. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aah5084 (2017). source
The Introduction (page not provided) identifies BRD4, a BET protein, as a transcriptional coactivator and reports that JQ1 prevented cardiac hypertrophy and left ventricular systolic dysfunction in a mouse pressure-overload model. The Discussion also describes BET bromodomain inhibitors as having cardioprotective properties. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Expression of the resident macrophage markers15,16 Lyve1, Folr2 and Timd4 were enriched in clusters 4 and 6, with Lyve1 and Folr2 also marking clusters 0, 2 and 3 (Fig. 1J and Extended Data Fig. 1C-E).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Partly supportedcites [15] Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29–39 (2019). sourceExperimental — accuracy not yet measured
The Discussion identifies TIMD4 and LYVE1 as resident cardiac macrophage markers. The Results section on recruited cardiac macrophage plasticity lists Folr2 among genes associated with mature macrophages, but does not specifically establish it as a resident marker. The cluster-enrichment pattern is presented as the citing paper’s own figure result, not as a finding attributed to this source. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [16] Dick, S. A. et al. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles. Sci. Immunol. 7, eabf7777 (2022). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Given the ability of myeloid cells to act as non-cell autonomous amplifiers of the stress-response through secreted factors12-14”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
What the sources say
- Not checked — no full text of the sourcecites [12] Korf-Klingebiel, M. et al. Myeloid-derived growth factor protects against pressure overload-induced heart failure by preserving sarco/endoplasmic reticulum Ca2+-ATPase expression in cardiomyocytes. Circulation 144, 1227–1240 (2021). source
- Not checked — no full text of the sourcecites [13] Reboll, M. R. et al. EMC10 (endoplasmic reticulum membrane protein complex subunit 10) is a bone marrow-derived angiogenic growth factor promoting tissue repair after myocardial infarction. Circulation 136, 1809–1823 (2017). source
- Partly supportedcites [14] Dobaczewski, M., Xia, Y., Bujak, M., Gonzalez-Quesada, C. & Frangogiannis, N. G. CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells. Am. J. Pathol. 176, 2177–2187 (2010). sourceExperimental — accuracy not yet measured
The Discussion describes inflammatory monocytes secreting cytokines and explains how inflammatory mediators may affect cardiomyocytes and worsen remodeling after myocardial infarction. This supports an effect on other cells through secreted factors, but the paper does not establish that myeloid cells amplify a general stress response. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
Every source the paper cites for this claim was checked and supports it.
In the paper
“As Cx3cr1 is not expressed in fibroblasts26 (Extended Data Fig. 1A), and therefore Brd4 is not deleted in this cell population (Extended Data Figs. 2B and 3B-D), the fibroblast gene expression changes reflect a non-cell autonomous effect.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
What the sources say
- Supportedcites [26] Heidt, T. et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ. Res. 115, 284–295 (2014). source
The citation is attached to the statement that Cx3cr1 is not expressed in fibroblasts, not to the subsequent Brd4-deletion result or non-cell-autonomous interpretation. In the Results section (Fig. 1B), the paper reports no Cx3cr1 reporter expression in cardiac fibroblasts; the supplied passage gives no page number. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the 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).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
What the sources say
- Partly supportedcites [27] Hanna, A., Humeres, C. & Frangogiannis, N. G. The role of Smad signaling cascades in cardiac fibrosis. Cell. Signal. 77, 109826 (2021). sourceExperimental — accuracy not yet measured
The ‘Smad signaling cascades in fibroblasts’ section (page not provided) describes Smad3 as a central signal promoting cardiac myofibroblast conversion and extracellular-matrix production, supporting the profibrotic role attributed to SMADs. The passages retrieved for RUNX1 and REL do not establish their roles in proinflammatory responses. The motif enrichment is presented as the citing paper’s own analysis, and MEOX1 carries a different citation. (LLM, conf=0.86)
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
The citation to this paper is attached to MEOX1, not to the citing authors’ motif analysis or the separately cited SMAD, RUNX1, and REL claims. In “MEOX1 regulates pro-fibrotic function,” the paper reports that Meox1 depletion reduces hallmarks of fibroblast activation and concludes that MEOX1 mediates the myofibroblast switch associated with fibrotic disease. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In human disease, stress-induced signaling converges in the nucleus, where chromatin receives, processes, and amplifies upstream inputs, ultimately leading to altered gene expression, maladaptive cell state transitions and organ dysfunction1.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Abstract
What the sources say
- Partly supportedcites [1] Badeaux, A. I. & Shi, Y. Emerging roles for chromatin as a signal integration and storage platform. Nat. Rev. Mol. Cell Biol. 14, 211–224 (2013). sourceExperimental — accuracy not yet measured
The Introduction (page not available) describes signaling reaching the nucleus and changing gene expression, while “Signal integration on histones” describes chromatin integrating multiple inputs into a transcriptional response. The Conclusion and perspectives links epigenetic signaling to disease and gives cancer-cell state changes as an example. It does not establish the full claimed chain from stress-induced signaling through chromatin amplification to organ dysfunction; its account of integration is partly speculative. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the 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)”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
What the sources say
- Supportedcites [4] Alexanian, M. et al. A transcriptional switch governs fibroblast activation in heart disease. Nature 595, 438–443 (2021). source
The ‘Stress-induced cis-regulation of Meox1’ section reports that JQ1, a BET inhibitor, suppressed TGFβ-induced Meox1 expression in cultured fibroblasts. The human cardiac fibroblast experiment is presented as the citing authors’ own confirmation, not as a result attributed to this source. (LLM, conf=0.93)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We captured 41,626 cells from Sham, TAC vehicle-treated (TAC), or TAC JQ1-treated (TAC JQ1) hearts, and identified 20 transcriptional clusters, including fibroblasts (Dcn+), myeloid cells (Lyz2+), endothelial cells (Fabp4+) and pericytes (Abcc9+) (Fig. 1C and Extended Data Fig. 1A).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The expression of the proinflammatory cytokine Il1b (Interleukin-1β) was particularly interesting as it was enriched in cluster 4 (Fig. 2I,J) and sensitive to cardiac stress and Brd4 deletion in Cx3cr1-positive cells (Fig. 2K).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 drives proinflammatory transcription
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among the top cluster 4 marker genes were several encoding the major histocompatibility complex (MHC) class 2 glycoproteins (also present in cluster 3) along with Il1b and Ccr2, both of which were enriched in cluster 4, even when compared to cluster 3 (Fig. 2G).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 drives proinflammatory transcription
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We ranked all genes expressed in the myeloid compartment by their correlation score using a stringent statistical threshold (p < 1e−6, corresponding to a correlation score < ± 5) and identified 22 anti-correlated (Fig. 1F) and 24 positively correlated (Fig. 1F and Extended Data Fig. 1B) with cardiac function.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that cluster 4 was expanded from Sham to TAC (9.3% to 14.9%) and reduced upon Brd4 deletion (14.9% to 2.5%) (Fig. 2E and Extended Data Fig. 2L).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 drives proinflammatory transcription
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We assessed the impact of Brd4 deletion in Cx3cr1-positive cells on monocyte infiltration post-TAC by flow cytometry 7 days after surgery which showed no significant effect on immune cell, monocyte, or macrophage numbers, but a trend suggesting a potential reduction in monocytes (Extended Data Fig. 2M).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 drives proinflammatory transcription
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By scRNA-seq, JQ1 reduced cells expressing Ccr2 (infiltrating macrophages) but did not affect cells expressing Timd4, Lyve1, and Folr2 (resident macrophages) (Extended Data Fig. 1G).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cx3cr1 and Il1b were co-expressed in cluster 1 (Fig. 1J), which was enriched in cells from TAC and depleted in Sham and TAC JQ1 conditions (Extended Data Fig. 1F).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We processed 10,450 immune cells and identified 16 transcriptomic clusters.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 drives proinflammatory transcription
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with Cx3cr1 and Il1b expression being negatively correlated with cardiac function (Fig. 1F), both genes were increased in TAC compared to Sham, and downregulated by JQ1 treatment (Fig. 1K).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Cx3cr1+ myeloid cells in heart failure
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, Cx3cr1 accessibility was almost entirely in cluster 4, as was accessibility of Il1b, one of the most dynamically regulated genes in the scRNA-seq analysis (Fig. 4D).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of the 15 super-enhancers with dynamic chromatin accessibility across conditions (Fig. 4I, top right quadrant), 10 had greater BRD4 binding in TAC, including the large enhancers proximal to Il1b, Mreg, Cdh26, and Cd83 (Extended Data Fig. 6J).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several motifs for p65/RELA were present within this 2.7kb distal region (Extended Data Fig. 9P), and p65/RELA ChIP-seq on human cardiac fibroblasts revealed direct binding at the MEOX1 human enhancer (Fig. 5D).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL1B led to a significant increase in α-smooth muscle (αSMA)-positive fibers, which was further increased when used in combination with TGFB compared to TGFB alone (Extended Data Fig. 9D).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We then scored accessibility across the dysregulated fibroblast genes in our snRNA-seq analysis and found that genes significantly upregulated in TAC versus TAC-Brd4KO displayed decreased accessibility in TAC-Brd4KO, indicating concordance between transcriptional and chromatin changes (Fig. 3M,N).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells from the TAC condition were greater in number in the Cx3cr1/Il1b accessible Cluster 4 relative to Sham, and Brd4 deletion was associated with a decrease in its composition (Extended Data Fig. 5C,D).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While most of the CRISPR deletions did not significantly affect LPS-induced Il1b induction, the deletion of peaks 5 and 6 reduced stress-induced expression (Fig. 4M).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“with cluster 3 associated with strong accessibility for CX3CR1, IL1B and CCR2 (Fig. 4P and Extended Data Fig. 8A), while clusters 5, 6 and 8 were associated with high accessibility for the resident macrophage markers TIMD4 and LYVE1 (Extended Data Fig. 8A).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Knockdown of IL1R1 impaired the contractility triggered by IL1B and TGFB+IL1B (Extended Data Fig. 9F-J), but had no effect in reducing contractility when TGFB was used alone (Extended Data Fig. 9I).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A group of 28,107 nuclei encompassing all the major cardiac cell populations was processed into 17 transcriptomic clusters (Fig. 3B, Extended Data Fig. 3A).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While cluster 0, the largest in number, was equally distributed between samples”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Il1b in Cx3cr1+ cells activates fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within the fibroblast population, we identified 7 transcriptional clusters encompassing 7,388 cells (Fig. 3E), with TAC and TAC-Brd4KO fibroblasts clustering separately (Fig. 3F).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We identified 21 clusters, and gene score signals of C1qa, Cd163, and Cd14 identified the monocyte/macrophage population, which was also accessible for Cx3cr1 (Extended Data Fig. 5A,B).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In vivo, antibody-mediated IL1B neutralization improved cardiac function and tissue fibrosis in heart failure.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1-positive macrophages ameliorates heart failure and significantly reduces fibroblast activation.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cluster 6 was associated with specific expression of fibroblast activation genes such as Postn, Meox1, Comp, Cilp, Mfap4, and Thbs4 (Fig. 3G, Extended Data Fig. 3E-G), and was depleted of TAC-Brd4KO fibroblasts (Extended Data Fig. 3H).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ones that decrease with TAC and increase with the deletion”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Identifying stress sensitive distal elements
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This results in 748 large enhancers.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Identifying stress sensitive distal elements
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Brd4 mRNA levels were significantly reduced in Cx3cr1CreERT2;Brd4flox/flox versus Brd4flox/flox animals only in CX3CR1Pos cells, while Brd4 expression was not affected in CMs, fibroblasts or endothelial cells (Extended Data Fig. 2A,B).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 function in Cx3cr1+ cells during heart failure
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the LPS-treated medium with IgG antibody increased fibroblast contractility, neutralizing IL1B significantly attenuated it, demonstrating that IL1B from myeloid cells modulates fibroblast contractile phenotype in a paracrine fashion (Fig. 5A).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: IL1B is a secreted factor that can influence other cell states through paracrine signaling.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“As expected, scATAC-seq annotated all major cell populations identified by snRNA-seq (Fig. 3I and Extended Data Fig. 4A).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > BRD4 in Cx3cr1+ cells activates fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, Il1b was one of the most sensitive genes to Brd4 deletion in Cx3cr1-expressing cells, suggesting direct regulation by BRD4 (Fig. 2H,K).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Stress-induced cis-regulation of Il1b
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“siRNA-mediated downregulation of MEOX1 abolished the increased fibroblast contractility induced by the combination of IL1B and TGFB (Fig. 5C and Extended Data Fig. 9L-O), suggesting dependency on MEOX1 for the activation of fibroblasts.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > IL1B drives profibrotic function via MEOX1
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodeling.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“One sample in one condition was excluded because the fibrosis percentage was greater than two standard deviations above the mean when considering all the data points across all conditions.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Fibrosis quantification
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All echocardiography analyses were performed blinded (mice were assigned an alphanumeric code).”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Mouse model of transverse aortic constriction, echocardiography
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To control for the large variance that can result from deriving coverage from a small number of cells, we only considered signal in regions in which at least two different samples had at least one read, and set a minimum threshold of 4e−6 for detectability of coverage”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Analysis of publicly available human scATAC-seq data
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A blinded approach (labeling samples with an alphanumeric code) was implemented for analyzing fibrosis.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Fibrosis quantification
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All protocols concerning animal use were approved by the Institutional Animal Care and Use Committees at the University of California, San Francisco and conducted in strict accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Animal models
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each construct was transfected in three technical replicates and at least 3 biological replicates were performed.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Luciferase reporter assays
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Before this study, the mechanism by which organ-level stress is sensed by cells to trigger downstream fibroblast activation was unknown.
“However, the mechanism by which organ-level stress is sensed by cells to trigger downstream fibroblast activation remains unknown.”
The paper relies on this without support.
IL1B is a secreted factor that can influence other cell states through paracrine signaling.
“Importantly, Il1b encodes a secreted factor (IL1B) that can influence other cell states via paracrine signaling.”
The paper relies on this without support.
In response to stress, chromatin remodeling can alter expression of secreted factors and thereby influence neighboring cells through non-cell autonomous mechanisms.
“In response to stress, chromatin remodeling can alter the expression of secreted factors thus influencing neighboring cells through non-cell autonomous mechanisms and fueling pathological crosstalk between diverse cellular compartments.”
The paper relies on this without support.
The molecular mechanisms governing crosstalk between chronic inflammation and tissue fibrosis are poorly understood.
“Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood.”
The paper relies on this without support.
Systemic neutralizing antibody administration blocked IL1B from various possible cellular sources.
“As systemic neutralizing antibody administration blocked IL1B from various possible cellular sources”
The paper relies on this without support.
Little is known about how inflammatory signals can influence fibroblast cell states in disease.
“little is known about how inflammatory signals can influence fibroblast cell states in disease.”
The paper relies on this without support.
Findings from the mouse TAC model and anti-IL1B treatment translate to human heart disease.
“IL1B antibody-mediated neutralization is sufficient to improve cardiac function in heart disease.”
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
“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 [30]
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
“They also show that anti-IL-1β mAb treatment leads to fewer POSTN fibroblasts, improved cardiac function and decreased cardiac fibrosis30.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [30]
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
“Consistent with our findings, the Srivastava laboratory has shown that Brd4 deletion in macrophages abrogates IL-1β signalling and suppresses fibroblast activation and fibrosis through a MEOX1-dependent regulatory mechanism in a pressure-overload model of HF30.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [30]
Experimental — accuracy not yet measuredThe 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 [30]
The cited source says what the claim attributes to it.
In the citing paper
“These findings are underscored by concurrent work establishing a role for MEOX1 in the pathogenesis of cardiac fibrosis30.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [30]
The cited source says what the claim attributes to it.
In the citing paper
“Consistent with these findings, concurrent work showed that anti-IL-1β mAb treatment improved cardiac function and reduced fibrosis in a TAC HF model30.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Statistics and reproducibility
“In all figures, the exact p-value is indicated if the p-value is higher than 0.0001.”
§ Chromatin Remodeling Drives Immune Cell-Fibroblast Communication in Heart Failure > Methods > Statistics and reproducibility
“For values lower than 0.001 we indicate P<0.0001.”
Citations
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Cited by
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Metadata
- Authors
- Alexanian, M., Padmanabhan, A., Nishino, T., Travers, J. G., Ye, L., Pelonero, A., Lee, C. Y., Sadagopan, N., Huang, Y., Auclair, K., Zhu, A., An, Y., Ekstrand, C. A., Martinez, C., Teran, B. G., Flanigan, W. R., Kim, C. K.-S., Lumbao-Conradson, K., Gardner, Z., Li, L., Costa, M. W., Jain, R., Charo, I., Combes, A. J., Haldar, S. M., Pollard, K. S., Vagnozzi, R. J., McKinsey, T. A., Przytycki, P. F., & Srivastava, D.
- Affiliations
- Gladstone Institutes (US)
- University of Colorado Anschutz (US)
- University of California, San Francisco (US)
- University of Pennsylvania (US)
- Amgen (United States) (US)
- Boston University (US)
- Corresponding author
- Alexanian, Michael
- ORCID
- Alexanian, Michael
- Padmanabhan, Arun
- Nishino, Tomohiro
- Travers, Joshua G.
- Ye, Lin
- Pelonero, Angelo
- Lee, Clara Youngna
- Huang, Yu
- An, Yuqian
- Ekstrand, Christina A.
- Martinez, Cassandra
- Flanigan, Will R.
- Kim, Charis Kee-Seon
- Lumbao-Conradson, Koya
- Gardner, Zachary
- Li, Li
- Costa, Mauro W.
- Jain, Rajan
- Combes, Alexis J.
- Haldar, Saptarsi M.
- Pollard, Katherine S.
- Vagnozzi, Ronald J.
- McKinsey, Timothy A.
- Przytycki, Pawel F.
- Srivastava, Deepak
- Venue
- Nature
- Published
- 2024-10-23
- Volume
- 635
- Issue
- 8038
- Pages
- 434-443
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11698514
- OpenAlex
- W4403680473
- Semantic Scholar
- 4068b221dac01063659a124623f00bb7bc087cc7
- Cited by
- 140
- References
- 57
- Citations by year
- 2026: 69 · 2025: 64 · 2024: 7
- FWCI
- 41.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- American Heart Association
- A.P. Giannini Foundation
- Tobacco-Related Disease Research Program
- Giannini Foundation of Agricultural Economics
- Frank A. Campini Foundation
- Sarnoff Cardiovascular Research Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186704)
- Italfarmaco
- National Institutes of Health
- Agency for Healthcare Research and Quality (R01HS015100)
- Japan Society for the Promotion of Science
- National Heart, Lung, and Blood Institute (R01HL147558, K99HL166708, R01HL116848, P01HL146366, R01HL150100, P01HL089707, R01HL127240, U01HL098179, R01HL150225, R01HL057181, K08HL157700, R01HL169578, R35HL166663)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119594)
- 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 › Genomics and Chromatin Dynamics
- Keywords
- heart failure, myocardial fibrosis, BRD4, chromatin remodeling, macrophages, CX3CR1+ macrophages, fibroblast activation, IL-1β, MEOX1, RelA/p65, chromatin accessibility, chronic inflammation, tissue remodeling
- MeSH terms
- CX3C Chemokine Receptor 1, Bromodomain Containing Proteins, Animals, Cell Communication, Chromatin, Enhancer Elements, Genetic, Female, Fibroblasts, Fibrosis, Heart Failure, Humans, Macrophages, Male, Mice, Inbred C57BL, Nuclear Proteins, Transcription Factors, Homeodomain Proteins, Cell Cycle Proteins, Chromatin Assembly and Disassembly, Mice, Transcription Factor RelA, Interleukin-1beta, Single-Cell Analysis
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.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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 ›
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