Universität zu Köln

Kleinenkuhnen, Niklas Peter (2023). Multi-omics analysis of the ageing liver. PhD thesis, Universität zu Köln.

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Abstract

This dissertation presents three manuscripts that originated from my work on the ageing liver. The first two manuscripts concentrate on integrative multi-omics ap-proaches, such as scATAC-seq and scRNA-seq, spatial transcriptomics, CUT&RUN sequencing and lipidomics. They reveal distinct ageing signatures within the murine liver, mainly in hepatocytes. The third manuscript introduces a new methodology for the analysis of spatial sequencing data, which was developed with the ageing liver as an intended application. The first manuscript, "Single-cell resolution unravels spatial alterations in metabo-lism, transcriptome, and epigenome of ageing liver", establishes how spatial loca-tion and microenvironmental changes impact the ageing trajectories of hepatocytes within liver tissue. Through the integration of spatial transcriptomics, single-cell ATAC- and RNA-seq, lipidomics, and functional assays, the study elucidates zonation-specific and age-related changes in the epigenome, transcriptome, and metabolic states. We identified a zonation-dependent shift in the epigenome and show that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs. From a functional perspective, periportal hepatocytes exhibited diminished mitochondrial fitness, whereas pericentral hepatocytes demonstrated an increased accumulation of large lipid droplets. The second manuscript, "Ageing is associated with increased chromatin accessibil-ity and reduced polymerase pausing in liver", examines the chromatin landscape of the ageing liver by using CUT&RUN for RNA polymerase mapping, integrated with ATAC-seq, RNA-seq, and NET-seq. The study reveals an increase in chromatin accessi-bility at promoter regions as a characteristic of ageing, which is not accompanied by a corresponding increase in transcriptional output. Ageing is also found to be associated with a decrease in promoter-proximal pausing of RNA Polymerase II. Our observations suggest that alterations in transcriptional regulation associated with ageing may be due to decreased stability of the pausing complex. The third manuscript, "Dimension reduction by spatial components analysis im-proves pattern detection in multivariate spatial data", introduces SPACO, a new statistical approach designed to enhance pattern recognition in multivariate spatial sequencing data. SPACO stands out by focusing on gene co-regulation and maximising local covariance. It provides a more sensitive and accurate test for the identification of genes with a spatial expression pattern. Moreover, the use of spatial components for gene denoising by SPACO boosts the effective linkage of histological observations with gene expression patterns, even in high-noise conditions.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Kleinenkuhnen, Niklas Peter niklas.kleku@icloud.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-715706
Date:	31 July 2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language Ageing UNSPECIFIED Computational biology UNSPECIFIED Bioinformatics UNSPECIFIED
Date of oral exam:	6 November 2023
Referee:	Name Academic Title Tresch, Achim Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/71570