A transcriptional switch governs fibroblast activation in heart disease

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 . Pharmaco...

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Veröffentlicht in:Nature (London) 2021-07, Vol.595 (7867), p.438-443
Hauptverfasser: Alexanian, Michael, Przytycki, Pawel F., Micheletti, Rudi, Padmanabhan, Arun, Ye, Lin, Travers, Joshua G., Gonzalez-Teran, Barbara, Silva, Ana Catarina, Duan, Qiming, Ranade, Sanjeev S., Felix, Franco, Linares-Saldana, Ricardo, Li, Li, Lee, Clara Youngna, Sadagopan, Nandhini, Pelonero, Angelo, Huang, Yu, Andreoletti, Gaia, Jain, Rajan, McKinsey, Timothy A., Rosenfeld, Michael G., Gifford, Casey A., Pollard, Katherine S., Haldar, Saptarsi M., Srivastava, Deepak
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container_end_page 443
container_issue 7867
container_start_page 438
container_title Nature (London)
container_volume 595
creator Alexanian, Michael
Przytycki, Pawel F.
Micheletti, Rudi
Padmanabhan, Arun
Ye, Lin
Travers, Joshua G.
Gonzalez-Teran, Barbara
Silva, Ana Catarina
Duan, Qiming
Ranade, Sanjeev S.
Felix, Franco
Linares-Saldana, Ricardo
Li, Li
Lee, Clara Youngna
Sadagopan, Nandhini
Pelonero, Angelo
Huang, Yu
Andreoletti, Gaia
Jain, Rajan
McKinsey, Timothy A.
Rosenfeld, Michael G.
Gifford, Casey A.
Pollard, Katherine S.
Haldar, Saptarsi M.
Srivastava, Deepak
description 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. BET proteins regulate a reversible transcriptional switch that governs fibroblast activation in heart disease through the transcription factor MEOX1.
doi_str_mv 10.1038/s41586-021-03674-1
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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. 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BET proteins regulate a reversible transcriptional switch that governs fibroblast activation in heart disease through the transcription factor MEOX1.</description><identifier>ISSN: 0028-0836</identifier><identifier>ISSN: 1476-4687</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03674-1</identifier><identifier>PMID: 34163071</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/106 ; 13/109 ; 13/89 ; 14/1 ; 38/109 ; 38/39 ; 38/89 ; 38/90 ; 38/91 ; 45/15 ; 45/90 ; 45/91 ; 631/208 ; 631/337 ; 64/60 ; Accessibility ; Animals ; Cardiomyocytes ; Cardiovascular disease ; Cardiovascular diseases ; Cell activation ; Cellular stress response ; Chromatin ; Chromatin - metabolism ; Coronary artery disease ; CRISPR ; Deoxyribonucleic acid ; Development and progression ; DNA ; Enhancer Elements, Genetic ; Epigenomics ; Fibroblasts ; Fibroblasts - cytology ; Fibrosis ; Gene expression ; Gene Expression Regulation ; Genetic aspects ; Genetic regulation ; Genetic transcription ; Genomics ; Health aspects ; Heart diseases ; Heart Diseases - genetics ; Heart failure ; Homeodomain Proteins - metabolism ; Humanities and Social Sciences ; Humans ; Kidneys ; Liver ; Liver diseases ; Lungs ; Mice ; multidisciplinary ; Pathogenesis ; Proteins ; Proteins - antagonists &amp; inhibitors ; Regulatory sequences ; RNA polymerase ; Science ; Science (multidisciplinary) ; Single-Cell Analysis ; Transcription Factors - metabolism ; Transcriptome ; Transforming Growth Factor beta - metabolism</subject><ispartof>Nature (London), 2021-07, Vol.595 (7867), p.438-443</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. 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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. 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BET proteins regulate a reversible transcriptional switch that governs fibroblast activation in heart disease through the transcription factor MEOX1.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/89</subject><subject>14/1</subject><subject>38/109</subject><subject>38/39</subject><subject>38/89</subject><subject>38/90</subject><subject>38/91</subject><subject>45/15</subject><subject>45/90</subject><subject>45/91</subject><subject>631/208</subject><subject>631/337</subject><subject>64/60</subject><subject>Accessibility</subject><subject>Animals</subject><subject>Cardiomyocytes</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Cell activation</subject><subject>Cellular stress response</subject><subject>Chromatin</subject><subject>Chromatin - metabolism</subject><subject>Coronary artery disease</subject><subject>CRISPR</subject><subject>Deoxyribonucleic 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transcriptional switch governs fibroblast activation in heart disease</title><author>Alexanian, Michael ; Przytycki, Pawel F. ; Micheletti, Rudi ; Padmanabhan, Arun ; Ye, Lin ; Travers, Joshua G. ; Gonzalez-Teran, Barbara ; Silva, Ana Catarina ; Duan, Qiming ; Ranade, Sanjeev S. ; Felix, Franco ; Linares-Saldana, Ricardo ; Li, Li ; Lee, Clara Youngna ; Sadagopan, Nandhini ; Pelonero, Angelo ; Huang, Yu ; Andreoletti, Gaia ; Jain, Rajan ; McKinsey, Timothy A. ; Rosenfeld, Michael G. ; Gifford, Casey A. ; Pollard, Katherine S. ; Haldar, Saptarsi M. ; Srivastava, 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Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alexanian, Michael</au><au>Przytycki, Pawel F.</au><au>Micheletti, Rudi</au><au>Padmanabhan, Arun</au><au>Ye, Lin</au><au>Travers, Joshua G.</au><au>Gonzalez-Teran, Barbara</au><au>Silva, Ana Catarina</au><au>Duan, Qiming</au><au>Ranade, Sanjeev S.</au><au>Felix, Franco</au><au>Linares-Saldana, Ricardo</au><au>Li, Li</au><au>Lee, Clara Youngna</au><au>Sadagopan, Nandhini</au><au>Pelonero, Angelo</au><au>Huang, Yu</au><au>Andreoletti, Gaia</au><au>Jain, Rajan</au><au>McKinsey, Timothy A.</au><au>Rosenfeld, Michael G.</au><au>Gifford, Casey A.</au><au>Pollard, Katherine S.</au><au>Haldar, Saptarsi M.</au><au>Srivastava, Deepak</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A transcriptional switch governs fibroblast activation in heart disease</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-07-15</date><risdate>2021</risdate><volume>595</volume><issue>7867</issue><spage>438</spage><epage>443</epage><pages>438-443</pages><issn>0028-0836</issn><issn>1476-4687</issn><eissn>1476-4687</eissn><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. BET proteins regulate a reversible transcriptional switch that governs fibroblast activation in heart disease through the transcription factor MEOX1.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34163071</pmid><doi>10.1038/s41586-021-03674-1</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-5660-2620</orcidid><orcidid>https://orcid.org/0000-0002-3480-5953</orcidid><orcidid>https://orcid.org/0000-0002-7684-3771</orcidid><orcidid>https://orcid.org/0000-0002-6204-3028</orcidid><orcidid>https://orcid.org/0000-0002-4297-7149</orcidid><orcidid>https://orcid.org/0000-0003-2657-825X</orcidid><orcidid>https://orcid.org/0000-0001-7968-9696</orcidid><orcidid>https://orcid.org/0000-0002-9402-4155</orcidid><orcidid>https://orcid.org/0000-0002-3360-6936</orcidid><orcidid>https://orcid.org/0000-0002-4336-8644</orcidid><orcidid>https://orcid.org/0000-0002-9870-6196</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0028-0836
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issn 0028-0836
1476-4687
1476-4687
language eng
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source MEDLINE; Nature; Alma/SFX Local Collection
subjects 13
13/1
13/106
13/109
13/89
14/1
38/109
38/39
38/89
38/90
38/91
45/15
45/90
45/91
631/208
631/337
64/60
Accessibility
Animals
Cardiomyocytes
Cardiovascular disease
Cardiovascular diseases
Cell activation
Cellular stress response
Chromatin
Chromatin - metabolism
Coronary artery disease
CRISPR
Deoxyribonucleic acid
Development and progression
DNA
Enhancer Elements, Genetic
Epigenomics
Fibroblasts
Fibroblasts - cytology
Fibrosis
Gene expression
Gene Expression Regulation
Genetic aspects
Genetic regulation
Genetic transcription
Genomics
Health aspects
Heart diseases
Heart Diseases - genetics
Heart failure
Homeodomain Proteins - metabolism
Humanities and Social Sciences
Humans
Kidneys
Liver
Liver diseases
Lungs
Mice
multidisciplinary
Pathogenesis
Proteins
Proteins - antagonists & inhibitors
Regulatory sequences
RNA polymerase
Science
Science (multidisciplinary)
Single-Cell Analysis
Transcription Factors - metabolism
Transcriptome
Transforming Growth Factor beta - metabolism
title A transcriptional switch governs fibroblast activation in heart disease
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