The Role of Suv4-20h1 in Cardiac and Pulmonary Development and Pathogenesis
The interdependence of heart and lung development is critical for proper morphogenesis and organ formation in mammals and has been demonstrated at cellular and physiological levels. Epigenetic control of the gene transcriptional network rules the program for cell specification, proliferation, migrat...
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| Format: | Dissertation |
| Sprache: | Englisch |
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Philipps-Universität Marburg
2024
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| Zusammenfassung: | The interdependence of heart and lung development is critical for proper morphogenesis and organ formation in mammals and has been demonstrated at cellular and physiological levels. Epigenetic control of the gene transcriptional network rules the program for cell specification, proliferation, migration and maturation during cardiopulmonary co-development. Sporadic mutations of SUV4-20H1, an enzyme that converts mono-methylated histone H4 lysine 20 to di-methylated form, have been identified in cohorts of human patients with congenital heart disease. However, proof that mutations in SUV4-20H1 cause congenital heart diseases has been missing. Moreover, the role of SUV4-20H1 in regulating cardiac and cardiopulmonary development by modulating chromatin structure and transcription has remained elusive.
In this study, I deciphered the role of SUV4-20H1 in controlling heart and lung development by inactivating Suv4-20h1 in various cardiopulmonary cell types in vivo. My findings demonstrate that Suv4-20h1 plays pivotal roles in ISL1+ cardiopulmonary progenitor cells, giving rise to smooth muscle cells and myofibroblasts in the postnatal lung. Loss of Suv4-20h1 in these cells leads to chronic obstructive pulmonary disease and pulmonary hypertension. I found that, SUV4-20H1 modulates H4K20me2 deposition at regulatory elements of genes involved in control of the redox state and in inflammatory responses, among others. Loss of H4K20me2 in Suv4-20h1 mutant cells results in accumulation of H4K20me1 and opening of the chromatin, which causes de-repression of multiple target genes. Expression of the mutant form of SUV4-20H1 found in human patients with congenital heart defects in mice recapitulated the human phenotype. Heart defects also developed in mice that still have an intact Suv4-20h1 allele, suggesting that the mutant form of SUV4-20H1 causes dominant-negative effects. Further studies revealed that SUV4-20H1 modulates the formation of phase-separated condensates and the association of the variable lamina-associated domain with the nuclear envelope, which is required to repress cardiac gene expression in a spatio-temporal manner.
In sum, my results unraveled the complex function of SUV4-20H1 in regulating gene expression by modulating enhancer activity and/or three-dimensional chromatin organization during heart and lung development. A deeper understanding of this key molecule may provide new perspectives for the treatment of pulmonary and cardiac diseases. |
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| DOI: | 10.17192/z2024.0464 |