A systematic dissection of the catalytic and non-catalytic functions of TET1 at the interface of epigenetic regulation

Stolz, Paul (2023): A systematic dissection of the catalytic and non-catalytic functions of TET1 at the interface of epigenetic regulation. Dissertation, LMU München: Fakultät für Biologie

Abstract

Mammalian DNA consists of millions of base pairs. To fit the DNA into the nucleus of a cell the DNA is condensed into chromosomes. The DNA is wrapped around an histone octamer forming nucleosomes which are the basis of chromatin. Chromatin is the physiological form of DNA and altered by various epigenetic mechanisms, such as DNA methylation, histone modifications and RNA modifications. During development epigenetic mechanisms drive lineage choices and cell identity. In this doctoral work we used next generation sequencing and CRISPR/Cas9 genome engineering to study different epigenetic mechanisms in mESCs. The main focus was to study the non-catalytic functions of the DNA demethylase TET1. I have found that TET1 is involved in heterochromatin formation and retroviral silencing independent of DNA demethylation (Publication I). In the scope of this doctoral work I contributed to other projects with the focus on epigenetic proteins in mESCs. First, description of the role of the UBL domain of UHRF1 in the interplay with DNMT1 and DNA maintenance methylation (Publication II). Second, identification of DPPA3 as a regulator of UHRF1 and critical for global DNA demethylation (Publication III). Third, discovery of TET1 and TET2 stage-specific roles in DNA demethylation during early embryonic development (Publication IV). Last, in the scope of this doctoral work I contributed to study the role and function of the novel RNA methyltransferases METTL5 and METTL6 in the field of epitranscriptomics. METTL5 was found to be a specific ribosomal RNA methyltransferase critical for pluripotency and differentiation (Publication V). METTL6 was discovered as a transfer RNA methyltransferase involved in cancer (Publication VI). In summary, this doctoral work investigated and described novel non-catalytic mechanisms of TET1 and studied various epigenetic modifiers and mechanisms at different epigenetic levels.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 6. Februar 2023
• 1. Bericht­erstatter:in: Leonhardt, Heinrich