| dc.contributor.advisor | Zelarayán, Laura C. PD Dr. | |
| dc.contributor.author | Iyer, Lavanya Muthukrishnan | |
| dc.date.accessioned | 2018-11-12T10:01:02Z | |
| dc.date.available | 2019-09-25T22:50:02Z | |
| dc.date.issued | 2018-11-12 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E4F9-6 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7112 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7112 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Wnt-TCF7L2-dependent transcriptional and chromatin dynamics in cardiac regeneration, homeostasis and disease | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Zelarayán, Laura C. PD Dr. | |
| dc.date.examination | 2018-09-26 | |
| dc.description.abstracteng | Wnt/β-catenin-dependent signaling pathway is indispensible for cardiac development, becoming quiescent in the normal adult heart, and re-activated in both regenerative responses post-injury and in cardiac hypertrophy and failure. Many studies have demonstrated the effect of its main nuclear effector- Transcription factor 7-like 2 (TCF7L2) in influencing chromatin landscapes in different malignancies. However, despite being widely studied in the heart, there was little or no evidence for the role of Wnt-TCF7L2 in directly governing cardiac chromatin homeostasis. To address this direct function, we generated transgenic, inducible murine model with cardiomyocytes (CM)-specific B-catenin stabilization, which led to heart failure. We observed increased TCF7L2 expression in both neonatal ((with a regenerative potential, at postnatal day 6 (P6)) as well as in diseased (both experimental and transgenic) cardiac ventricular tissue. Genome-wide mapping of TCF7L2 targets revealed differential occupancies- proximal in neonatal and distal in diseased cardiac ventricles. Integration of genomic with transcriptomic data showed that TCF7L2 directly bound to and primarily regulated aldehyde and fatty acid metabolism in the neonatal; and cardiac developmental and angiogenesis processes in the diseased adult hearts, thereby discerning these two cardiac states. Our search for TCF7L2-cardiac interaction partners revealed remarkable context-specific associations. We identified GATA4 and KLF15 as components of the Wnt-cardiac complex, which repress the pathway for homeostasis in the healthy heart. Conversely, this Wnt-GATA4 interaction was lost in disease progression. Interestingly, despite a high Wnt activity, Wnt-GATA4 interaction persisted in neonatal hearts, suggesting the involvement of other co-factors that can provide this regenerative context. This led to the identification of associations between the Hippo and Wnt pathways in neonatal hearts. Furthermore, lack of cardiac Wnt repressors like KLF15 resulted in gradual cardiac dysfunction, unearthing a so far uncharacterized gene Shisa3, in this process. Genomic, transcriptomic and experimental data unraveled that Shisa3 is a cardiac developmental gene, which is reactivated in heart disease, upon loss of KLF15 and activation of Wnt signaling. Our experiments showed that Shisa3 belonged to the endothelial reprogramming process during pathological cardiac remodeling. Altogether, results from this dissertation dissected stage-specific nuclear roles of Wnt-TCF7L2, thereby identifying novel cardiac target genes and previously unknown interaction partners. These findings can potentially form the basis for therapeutic interventions promoting cardiac regenerative responses, in a safe, targeted manner. | de |
| dc.contributor.coReferee | Johnsen, Steven Prof. Dr. | |
| dc.subject.eng | chromatin | de |
| dc.subject.eng | heart | de |
| dc.subject.eng | Wnt-pathway | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E4F9-6-5 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Medizin (PPN619874732) | de |
| dc.subject.gokfull | Molekularbiologie {Medizin} (PPN619875186) | de |
| dc.description.embargoed | 2019-09-25 | |
| dc.identifier.ppn | 1040426891 | |