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 |
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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 |
format | Article |
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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.</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 & 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. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 15, 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c742t-8eebba6e6dbdd3678e2e26ad0359ea978c877ab25b9005682ba6cfbc1edab7393</citedby><cites>FETCH-LOGICAL-c742t-8eebba6e6dbdd3678e2e26ad0359ea978c877ab25b9005682ba6cfbc1edab7393</cites><orcidid>0000-0002-5660-2620 ; 0000-0002-3480-5953 ; 0000-0002-7684-3771 ; 0000-0002-6204-3028 ; 0000-0002-4297-7149 ; 0000-0003-2657-825X ; 0000-0001-7968-9696 ; 0000-0002-9402-4155 ; 0000-0002-3360-6936 ; 0000-0002-4336-8644 ; 0000-0002-9870-6196</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34163071$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alexanian, Michael</creatorcontrib><creatorcontrib>Przytycki, Pawel F.</creatorcontrib><creatorcontrib>Micheletti, Rudi</creatorcontrib><creatorcontrib>Padmanabhan, Arun</creatorcontrib><creatorcontrib>Ye, Lin</creatorcontrib><creatorcontrib>Travers, Joshua G.</creatorcontrib><creatorcontrib>Gonzalez-Teran, Barbara</creatorcontrib><creatorcontrib>Silva, Ana Catarina</creatorcontrib><creatorcontrib>Duan, Qiming</creatorcontrib><creatorcontrib>Ranade, Sanjeev S.</creatorcontrib><creatorcontrib>Felix, Franco</creatorcontrib><creatorcontrib>Linares-Saldana, Ricardo</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Lee, Clara Youngna</creatorcontrib><creatorcontrib>Sadagopan, Nandhini</creatorcontrib><creatorcontrib>Pelonero, Angelo</creatorcontrib><creatorcontrib>Huang, Yu</creatorcontrib><creatorcontrib>Andreoletti, Gaia</creatorcontrib><creatorcontrib>Jain, Rajan</creatorcontrib><creatorcontrib>McKinsey, Timothy A.</creatorcontrib><creatorcontrib>Rosenfeld, Michael G.</creatorcontrib><creatorcontrib>Gifford, Casey A.</creatorcontrib><creatorcontrib>Pollard, Katherine S.</creatorcontrib><creatorcontrib>Haldar, Saptarsi M.</creatorcontrib><creatorcontrib>Srivastava, Deepak</creatorcontrib><title>A transcriptional switch governs fibroblast activation in heart disease</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><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.</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 acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>Enhancer Elements, Genetic</subject><subject>Epigenomics</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibrosis</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genetic aspects</subject><subject>Genetic regulation</subject><subject>Genetic transcription</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Heart diseases</subject><subject>Heart Diseases - genetics</subject><subject>Heart failure</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Kidneys</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Lungs</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Pathogenesis</subject><subject>Proteins</subject><subject>Proteins - antagonists & 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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, Deepak</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c742t-8eebba6e6dbdd3678e2e26ad0359ea978c877ab25b9005682ba6cfbc1edab7393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13</topic><topic>13/1</topic><topic>13/106</topic><topic>13/109</topic><topic>13/89</topic><topic>14/1</topic><topic>38/109</topic><topic>38/39</topic><topic>38/89</topic><topic>38/90</topic><topic>38/91</topic><topic>45/15</topic><topic>45/90</topic><topic>45/91</topic><topic>631/208</topic><topic>631/337</topic><topic>64/60</topic><topic>Accessibility</topic><topic>Animals</topic><topic>Cardiomyocytes</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>Cell activation</topic><topic>Cellular stress response</topic><topic>Chromatin</topic><topic>Chromatin - metabolism</topic><topic>Coronary artery disease</topic><topic>CRISPR</topic><topic>Deoxyribonucleic acid</topic><topic>Development and progression</topic><topic>DNA</topic><topic>Enhancer Elements, Genetic</topic><topic>Epigenomics</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibrosis</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genetic aspects</topic><topic>Genetic regulation</topic><topic>Genetic transcription</topic><topic>Genomics</topic><topic>Health aspects</topic><topic>Heart diseases</topic><topic>Heart Diseases - genetics</topic><topic>Heart failure</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Kidneys</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>Lungs</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Pathogenesis</topic><topic>Proteins</topic><topic>Proteins - antagonists & inhibitors</topic><topic>Regulatory sequences</topic><topic>RNA polymerase</topic><topic>Science</topic><topic>Science 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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> |
fulltext | fulltext |
identifier | ISSN: 0028-0836 |
ispartof | Nature (London), 2021-07, Vol.595 (7867), p.438-443 |
issn | 0028-0836 1476-4687 1476-4687 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8341289 |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T07%3A01%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20transcriptional%20switch%20governs%20fibroblast%20activation%20in%20heart%20disease&rft.jtitle=Nature%20(London)&rft.au=Alexanian,%20Michael&rft.date=2021-07-15&rft.volume=595&rft.issue=7867&rft.spage=438&rft.epage=443&rft.pages=438-443&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03674-1&rft_dat=%3Cgale_pubme%3EA668389778%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2552297348&rft_id=info:pmid/34163071&rft_galeid=A668389778&rfr_iscdi=true |