Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis.

التفاصيل البيبلوغرافية
العنوان: Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis.
المؤلفون: Alexanian M; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA.; Department of Pediatrics, University of California, San Francisco; San Francisco, CA, USA., Padmanabhan A; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA.; Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA.; Chan Zuckerberg Biohub; San Francisco, CA, USA., Nishino T; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Travers JG; Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Ye L; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Lee CY; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA.; Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA., Sadagopan N; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA.; Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA., Huang Y; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Pelonero A; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Auclair K; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Zhu A; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Teran BG; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Flanigan W; Gladstone Institutes; San Francisco, CA, USA.; UC Berkeley-UCSF Joint Program in Bioengineering; Berkeley, CA, USA., Kim CK; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Lumbao-Conradson K; Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Costa M; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA., Jain R; Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA., Charo I; ChemoCentryx; Mountain View, CA, USA., Haldar SM; Gladstone Institutes; San Francisco, CA, USA.; Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA.; Amgen Research, Cardiometabolic Disorders; South San Francisco, CA, USA., Pollard KS; Gladstone Institutes; San Francisco, CA, USA.; Chan Zuckerberg Biohub; San Francisco, CA, USA.; Institute for Computational Health Sciences, University of California, San Francisco; San Francisco, CA, USA.; Department of Epidemiology & Biostatistics, University of California, San Francisco; San Francisco, CA, USA.; Institute for Human Genetics, University of California, San Francisco; San Francisco, CA, USA., Vagnozzi RJ; Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., McKinsey TA; Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Przytycki PF; Gladstone Institutes; San Francisco, CA, USA.; Faculty of Computing & Data Sciences, Boston University; Boston, MA, USA., Srivastava D; Gladstone Institutes; San Francisco, CA, USA.; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA.; Department of Pediatrics, University of California, San Francisco; San Francisco, CA, USA.; Department of Biochemistry and Biophysics, University of California, San Francisco; San Francisco, CA, USA.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 07. Date of Electronic Publication: 2023 Jan 07.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1 -positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1 -positive cells identified a large enhancer proximal to Interleukin-1 beta ( Il1b) , and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1 , resulting in a profibrotic response in human cardiac fibroblasts. In vivo , antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1 , inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.
معلومات مُعتمدة: K08 HL157700 United States HL NHLBI NIH HHS; K99 HL166708 United States HL NHLBI NIH HHS; R01 HL139783 United States HL NHLBI NIH HHS; R35 HL166663 United States HL NHLBI NIH HHS
تواريخ الأحداث: Date Created: 20230130 Latest Revision: 20240517
رمز التحديث: 20240517
مُعرف محوري في PubMed: PMC9881961
DOI: 10.1101/2023.01.06.522937
PMID: 36711864
قاعدة البيانات: MEDLINE
الوصف
DOI:10.1101/2023.01.06.522937