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Nitsch, S.

The impact of histone H4 lysine 16 acylations on chromatin dynamics and their links to acyl-CoA metabolism.

München, Ludwig-Maximilians-Universität, Fakultät für Biologie, Diss., 2023, 134 S.
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DNA can be wrapped around a histone octamer forming a nucleosome which is the smallest unit of chromatin. Chromatin is the storage form of genomic information in eukaryotic cells and its accessibility and function can be regulated by various post-translational modifications on histones. For example, acetylations on lysine residues in the histone tail or core regions are linked to open and accessible chromatin which allows active gene expression. In the last decade, multiple non-acetyl short-chain acylations on histone lysines deriving from corresponding metabolic intermediates (short-chain acyl-CoAs) were discovered. Histone acylations might therefore be able to integrate the metabolic state of a cell and fine-tune chromatin dynamics and gene expression. A detailed understanding of the interplay between metabolism and the epigenome remains elusive. In this thesis, we first aimed to understand how histone acylations can regulate chromatin architecture. For our site of interest, we chose H4K16 due to its well-established role in higher- order chromatin formation. Via different in vitro studies we revealed how H4K16ac, H4K16pr, and H4K16bu can fine-tune internucleosomal interactions and nucleosomal stacking. Overall, all three acylations show a similar tendency but to a different degree which was further reflected in the stimulation efficiency of transcription in vitro. We were also able to identify the main H4K16 acetyltransferase MOF as a propionyl- and butyryltransferase in cellulo and further demonstrated acylation-specific binding of SIRT3. In addition, we observed how the nuclear distribution of H4K16 acylations is involved in stem cell fate decisions during hHSCs aging processes. Our studies on the genomic distribution of H4K16 acylations in mESCs revealed a specific enrichment of these modifications which might drive different gene expression programs. Our in vivo studies using mouse models for metabolic diseases demonstrated that histone acylations can actually reflect changes of metabolic intermediates. Alterations in the acyl-CoA levels can also influence the acylation/acetylation ratio suggesting that the combination of acylations rather than changes of a single acylation define their role in regulating chromatin dynamics. In addition, we further speculate that histone acylations can serve as a reservoir for short-chain fatty acids during aberrant metabolic fluctuations in order to protect the cell from toxic accumulations of metabolic intermediates.
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Publication type Other: Thesis
Thesis type Doctoral thesis
Quellenangaben Volume: , Issue: , Pages: 134 S. Article Number: , Supplement: ,
University Ludwig-Maximilians-Universität
University place München
Faculty Fakultät für Biologie
Institute(s) Institute of Functional Epigenetics (IFE)