Zelarayan, Laura Cecilia

[["dc.bibliographiccitation.firstpage","1537"],["dc.bibliographiccitation.issue","6562"],["dc.bibliographiccitation.journal","Science"],["dc.bibliographiccitation.lastpage","1540"],["dc.bibliographiccitation.volume","373"],["dc.contributor.author","Chen, Yanpu"],["dc.contributor.author","Lüttmann, Felipe F."],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Schöler, Hans R."],["dc.contributor.author","Zelarayán, Laura C."],["dc.contributor.author","Kim, Kee-Pyo"],["dc.contributor.author","Haigh, Jody J."],["dc.contributor.author","Kim, Johnny"],["dc.contributor.author","Braun, Thomas"],["dc.date.accessioned","2021-10-01T09:58:23Z"],["dc.date.available","2021-10-01T09:58:23Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1126/science.abg5159"],["dc.identifier.pmid","34554778"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90052"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/404"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation.eissn","1095-9203"],["dc.relation.issn","0036-8075"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.title","Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.lastpage","24"],["dc.bibliographiccitation.volume","126"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Carroll, Kelli J."],["dc.contributor.author","Iyer, Lavanya M."],["dc.contributor.author","McAnally, John R."],["dc.contributor.author","Tan, Wei"],["dc.contributor.author","Liu, Ning"],["dc.contributor.author","Noack, Claudia"],["dc.contributor.author","Shomroni, Orr"],["dc.contributor.author","Salinas, Gabriela"],["dc.contributor.author","Groß, Julia"],["dc.contributor.author","Herzog, Nicole"],["dc.contributor.author","Doroudgar, Shirin"],["dc.contributor.author","Bassel-Duby, Rhonda"],["dc.contributor.author","Zimmermann, Wolfram-H."],["dc.contributor.author","Zelarayán, Laura C."],["dc.date.accessioned","2020-12-10T18:38:00Z"],["dc.date.available","2020-12-10T18:38:00Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1161/CIRCRESAHA.118.314522"],["dc.identifier.pmid","31730408"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77162"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/332"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.title","CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","53"],["dc.bibliographiccitation.lastpage","61"],["dc.bibliographiccitation.seriesnr","2573"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Zelarayán, Laura C."],["dc.contributor.editor","Ishikawa, Kiyotake"],["dc.date.accessioned","2022-09-01T09:51:07Z"],["dc.date.available","2022-09-01T09:51:07Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1007/978-1-0716-2707-5_5"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113885"],["dc.notes.intern","DOI-Import GROB-597"],["dc.publisher","Springer US"],["dc.publisher.place","New York, NY"],["dc.relation.crisseries","Methods in Molecular Biology"],["dc.relation.eisbn","978-1-0716-2707-5"],["dc.relation.isbn","978-1-0716-2706-8"],["dc.relation.ispartof","Cardiac Gene Therapy : Methods and Protocols"],["dc.title","Enhancing Cardiomyocyte Transcription Using In Vivo CRISPR/Cas9 Systems"],["dc.type","book_chapter"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S1873506121003202"],["dc.bibliographiccitation.firstpage","102473"],["dc.bibliographiccitation.journal","Stem Cell Research"],["dc.bibliographiccitation.volume","55"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Cyganek, Lukas"],["dc.contributor.author","Zelarayán, Laura Cecilia"],["dc.date.accessioned","2021-08-12T07:44:46Z"],["dc.date.available","2021-08-12T07:44:46Z"],["dc.date.issued","2021"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.1016/j.scr.2021.102473"],["dc.identifier.pii","S1873506121003202"],["dc.identifier.pmid","34343828"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88289"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/333"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/400"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation","SFB 1002 | INF: Unterstützung der SFB 1002 Forschungsdatenintegration, -visualisierung und -nachnutzung"],["dc.relation.issn","1873-5061"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.relation.workinggroup","RG Cyganek (Stem Cell Unit)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","Establishment of two homozygous CRISPR interference (CRISPRi) knock-in human induced pluripotent stem cell (hiPSC) lines for titratable endogenous gene repression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","Suppl_1"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.volume","129"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Rosa, Kim"],["dc.contributor.author","Rocha, Cheila"],["dc.contributor.author","Jassyk, Mareike"],["dc.contributor.author","Doroudgar, Shirin"],["dc.contributor.author","Mueller, Oliver"],["dc.contributor.author","Cyganek, Lukas"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Zelarayan, Laura Cecilia"],["dc.date.accessioned","2022-03-01T11:43:55Z"],["dc.date.available","2022-03-01T11:43:55Z"],["dc.date.issued","2021"],["dc.description.abstract","Transcriptional changes in cardiomyocytes drive heart failure progression, however, precise control over endogenous gene expression remains challenging. The expression of Krueppel-like factor 15 ( KLF15 ), an evolutionary conserved nuclear and cardiomyocyte specific inhibitor of WNT/CTNNB1 signalling in the heart, is lost upon cardiac remodelling, and accompanied by aberrantly active WNT/CTNNB1 resulting in heart failure progression. We investigated KLF15 expression dynamics employing CRISPR/Cas9-based tools in mouse cardiomyocytes in vivo and in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) under the hypothesis that re-establishment of KLF15 levels in myocardial stress conditions prevents heart failure progression. Using a mouse model expressing enzymatically inactive Cas9 (dCas9) fused to transcriptional activators (VPR) under Myh6 -promoter control, we activated Klf15 in a murine pressure overload model by transverse aortic constriction. Delivery of Klf15 gRNAs targeted to the Klf15 promoter region via AAV9 induced Klf15 expression sufficiently to re-normalize Klf15 expression to transcript levels comparable to sham surgery hearts. This was accompanied by reduced decrease of fractional shortening as well as reduced cardiomyocyte hypertrophy in stressed Klf15 re-activated hearts compared to non-trageted (NT) gRNA hearts (n=3-8 per group, echo data from 4 and 8 weeks post-surgery). We achieved titratable KLF15 activation in dCas9VPR transgenic hiPSC-CM by selection of single and multiple gRNAs (n=3-4 replicates) and used these cells to generate human engineered myocardium by combining hiPSC-CM and fibroblasts which we subjected to isometric contractions in order to induce mechanical stress, which resulted in KLF15 expressional decrease in line with our in vivo data. This transcriptional loss was rescued in CRISPR/dCas9VPR hiPSC-CM targeted to the KLF15 locus compared to controls (n=6-9/2/4 tissues per group/casting sessions/differentiations). Additionally, TGFB1 induced cardiomyocyte stress resulted in decreased KLF15 expression levels in 2D hiPSC-CM cultures which were rescued by dCas9VPR- KLF15 targeting (n=3 experiments). In conclusion, we report controllable gene activity by CRISPR/dCas9VPR to restore the loss of KLF15 in stressed mouse and human cardiomyocytes. We furthermore evaluate the potential to gain full control over gene dose titratability with these models to validate and define novel therapeutic targets for the prevention of heart failure progression."],["dc.description.abstract","Transcriptional changes in cardiomyocytes drive heart failure progression, however, precise control over endogenous gene expression remains challenging. The expression of Krueppel-like factor 15 ( KLF15 ), an evolutionary conserved nuclear and cardiomyocyte specific inhibitor of WNT/CTNNB1 signalling in the heart, is lost upon cardiac remodelling, and accompanied by aberrantly active WNT/CTNNB1 resulting in heart failure progression. We investigated KLF15 expression dynamics employing CRISPR/Cas9-based tools in mouse cardiomyocytes in vivo and in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) under the hypothesis that re-establishment of KLF15 levels in myocardial stress conditions prevents heart failure progression. Using a mouse model expressing enzymatically inactive Cas9 (dCas9) fused to transcriptional activators (VPR) under Myh6 -promoter control, we activated Klf15 in a murine pressure overload model by transverse aortic constriction. Delivery of Klf15 gRNAs targeted to the Klf15 promoter region via AAV9 induced Klf15 expression sufficiently to re-normalize Klf15 expression to transcript levels comparable to sham surgery hearts. This was accompanied by reduced decrease of fractional shortening as well as reduced cardiomyocyte hypertrophy in stressed Klf15 re-activated hearts compared to non-trageted (NT) gRNA hearts (n=3-8 per group, echo data from 4 and 8 weeks post-surgery). We achieved titratable KLF15 activation in dCas9VPR transgenic hiPSC-CM by selection of single and multiple gRNAs (n=3-4 replicates) and used these cells to generate human engineered myocardium by combining hiPSC-CM and fibroblasts which we subjected to isometric contractions in order to induce mechanical stress, which resulted in KLF15 expressional decrease in line with our in vivo data. This transcriptional loss was rescued in CRISPR/dCas9VPR hiPSC-CM targeted to the KLF15 locus compared to controls (n=6-9/2/4 tissues per group/casting sessions/differentiations). Additionally, TGFB1 induced cardiomyocyte stress resulted in decreased KLF15 expression levels in 2D hiPSC-CM cultures which were rescued by dCas9VPR- KLF15 targeting (n=3 experiments). In conclusion, we report controllable gene activity by CRISPR/dCas9VPR to restore the loss of KLF15 in stressed mouse and human cardiomyocytes. We furthermore evaluate the potential to gain full control over gene dose titratability with these models to validate and define novel therapeutic targets for the prevention of heart failure progression."],["dc.identifier.doi","10.1161/res.129.suppl_1.MP217"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102874"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4571"],["dc.relation.issn","0009-7330"],["dc.title","Abstract MP217: Nuclease-deficient Cas9 Transcription Factors Restore Krueppel-like Factor 15 Expression In Stressed Mouse And Human Cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S1873506121003652"],["dc.bibliographiccitation.firstpage","102518"],["dc.bibliographiccitation.journal","Stem Cell Research"],["dc.bibliographiccitation.volume","56"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Cyganek, Lukas"],["dc.contributor.author","Zelarayán, Laura Cecilia"],["dc.date.accessioned","2021-12-01T09:23:17Z"],["dc.date.available","2021-12-01T09:23:17Z"],["dc.date.issued","2021"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.1016/j.scr.2021.102518"],["dc.identifier.pii","S1873506121003652"],["dc.identifier.pmid","34481190"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/94607"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/434"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/418"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-478"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation","SFB 1002 | INF: Unterstützung der SFB 1002 Forschungsdatenintegration, -visualisierung und -nachnutzung"],["dc.relation.issn","1873-5061"],["dc.relation.workinggroup","RG Cyganek (Stem Cell Unit)"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","Establishment of a second generation homozygous CRISPRa human induced pluripotent stem cell (hiPSC) line for enhanced levels of endogenous gene activation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","101944"],["dc.bibliographiccitation.journal","Stem Cell Research"],["dc.bibliographiccitation.volume","48"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Argyriou, Loukas"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Cyganek, Lukas"],["dc.contributor.author","Zelarayán, Laura Cecilia"],["dc.date.accessioned","2021-06-01T10:49:55Z"],["dc.date.available","2021-06-01T10:49:55Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1016/j.scr.2020.101944"],["dc.identifier.pmid","33038615"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17612"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/86460"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/366"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.notes.intern","Merged from goescholar"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation.issn","1873-5061"],["dc.relation.workinggroup","RG Cyganek (Stem Cell Unit)"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Generation of homozygous CRISPRa human induced pluripotent stem cell (hiPSC) lines for sustained endogenous gene activation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1804"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","Journal of the American College of Cardiology"],["dc.bibliographiccitation.lastpage","1819"],["dc.bibliographiccitation.volume","74"],["dc.contributor.author","Noack, Claudia"],["dc.contributor.author","Iyer, Lavanya M."],["dc.contributor.author","Liaw, Norman Y."],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Khadjeh, Sara"],["dc.contributor.author","Wagner, Eva"],["dc.contributor.author","Woelfer, Monique"],["dc.contributor.author","Zafiriou, Maria-Patapia"],["dc.contributor.author","Milting, Hendrik"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Streckfuss-Boemeke, Katrin"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Zelarayán, Laura C."],["dc.date.accessioned","2020-12-10T14:24:44Z"],["dc.date.available","2020-12-10T14:24:44Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1016/j.jacc.2019.07.076"],["dc.identifier.pmid","31582141"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16513"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/72339"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/283"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","KLF15-Wnt–Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2850"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","2867"],["dc.bibliographiccitation.volume","46"],["dc.contributor.author","Iyer, Lavanya M"],["dc.contributor.author","Nagarajan, Sankari"],["dc.contributor.author","Woelfer, Monique"],["dc.contributor.author","Schoger, Eric"],["dc.contributor.author","Khadjeh, Sara"],["dc.contributor.author","Zafiriou, Maria Patapia"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Pang, Sze Ting"],["dc.contributor.author","Weber, Tobias"],["dc.contributor.author","Rathjens, Franziska S."],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Toischer, Karl"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Noack, Claudia"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Zelarayán, Laura C."],["dc.date.accessioned","2018-04-23T11:47:57Z"],["dc.date.available","2018-04-23T11:47:57Z"],["dc.date.issued","2018"],["dc.description.abstract","Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675-β-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-β-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of β-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2–5 and GATA4 in stabilized-β-catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/β-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing β-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/β-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway."],["dc.description.sponsorship","Open-Access-Publikatinsfonds 2018"],["dc.identifier.doi","10.1093/nar/gky049"],["dc.identifier.gro","3142314"],["dc.identifier.pmid","29394407"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15089"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13447"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/201"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt"],["dc.relation","SFB 1002 | C07: Kardiomyozyten Wnt/β-catenin Komplex Aktivität im pathologischen Herz-Remodeling - als gewebespezifischer therapeutischer Ansatz"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation","SFB 1002 | INF: Unterstützung der SFB 1002 Forschungsdatenintegration, -visualisierung und -nachnutzung"],["dc.relation.issn","0305-1048"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.relation.workinggroup","RG Toischer (Kardiales Remodeling)"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/4.0"],["dc.title","A context-specific cardiac β-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]