The role of sirtuins in epigenetic regulation

Zhao, Pin (2019): The role of sirtuins in epigenetic regulation. Dissertation, LMU München: Fakultät für Biologie

Abstract

Epigenetic mechanisms regulating gene expression mainly involve DNA methylation, histone modification, and non-coding RNAs. Disruption of these mechanisms may lead to cancer, complicated disorders such as behavioral disorders, amnesia, autoimmune disease, and addiction. DNA methylation is a widespread modification found in various species, which is produced by DNA methyltransferases (DNMTs), including Dnmt1, Dnmt2, Dnmt3a, Dnmt3b and Dnmt3L, and also considered as a stable gene-silencing mechanism. Specifically, the inhibition of gene transcription occurs, either by blocking the binding of transcriptional factors or through the recruitment of methylated DNA binding domain proteins. However, DNA methylation is also linked with histone modifications. Histones undergo a series of covalent modifications, like methylation, acetylation, ubiquitination, phosphorylation, and sumoylation. Furthermore, histone modifications are determined by the substrate specificity of the enzymes as well as enzymes that remove these marks. Among these modifications, histone acetylation is regarded as one of the marks for transcriptional activation and deacetylation of histone is closely associated with gene repression. In this work, we found that the nicotine adenine dinucleotide (NAD+)-dependent deacetylase sirtuins family is involved in epigenetic regulation, and connects histone deacetylation with DNA methylation. On the one hand, Sirt1 can interact with non-histone proteins, like Dnmt1 and Uhrf1, and influence protein stability and DNA methylation. Sirt1 mediated deacetylation stabilizes Uhrf1 in combination with the deubiquitinase Usp7. Functionally, deacetylation of Uhrf1 is a prerequisite for Uhrf1 to be phosphorylated by Cdk2 and enter into S phase of the cell cycle. The expression level of Uhrf1 fluctuates in different phases of the cell cycle and plays a crucial role in the regulation of DNA methylation. On the other hand, Sirtuins have been reported to deacetylate various substrates of histones, such as H3K9ac, H3K14ac, H4K16ac, and H1K6ac (Imai et al., 2000; Vaquero et al., 2004). Not only Sirt7 is a highly selective H3K18ac deacetylase for maintaining cellular transformation, but also Sirt1, Sirt2, and Sirt6 can deacetylate H3K18ac and regulate metabolism by downregulating some target genes. Significantly, these genes are regulated via a transcriptional factor, Hif1a, which provides new insights into therapies and metabolic diseases. Specifically, these genes are downregulated via the increased DNA methylation because sirtuins-mediated H3K18 deacetylation promotes Uhrf1-associated ubiquitination of H3K18, which is essential for Dnmt1 binding and DNA methylation (Qin et al., 2015a). Taken together, our data suggest that H3K18 acetylation, as one of the common histone substrate of sirtuin proteins, is enriched at the transcription start site (TSS) of active and poised genes, offends DNA methylation and thereby promotes transcriptional activation of these genes.

• 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: 18. März 2019
• 1. Bericht­erstatter:in: Leonhardt, Heinrich