<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops"^^ . "A long-standing aim in biology is to elucidate how the genome is tightly compacted inside the eukaryotic nucleus while still retaining its capacity to orchestrate the correct functionality of the cell. While years of research have revealed that this three-dimensional structuring of DNA plays a major role in the transcriptional regulation, most of the existing studies have focused on long-range chromatin interactions, which are mainly established by the CCCTC-binding factor (CTCF), rarely centring at the gene level. Furthermore, our current knowledge on the interplay between structure and function remains largely descriptive with little mechanistic insight. In this dissertation I present three distinct computational studies which integrate multiple levels of molecular phenotype data in an attempt to gain further insights into the influence of chromatin organisation in (i) splicing regulation, (ii) in how distal genetic variants convey their signal, (iii) and an overall view of the misregulation of chromatin compaction in ageing stem cells.\r\nFirstly, I describe a novel splicing mechanism whereby CTCF-mediated DNA- loops that are formed within genes facilitate exon inclusion. My results provide substantial evidence that intragenic loops regulate exon usage and that CTCF binding can be affected either by genetic variation across individuals or by the epigenomic landscape in different cell lines. Those exons being CTCF-regulated frequently overlap annotated protein domains and are enriched for being involved in cellular stress-response and signalling pathways. In summary, this study provides strong evidence for alternative exon usage being regulated by chromatin structure, and thus increases our understanding of functional consequences underlying variation in chromatin architecture.\r\nIn a second study, I show initial efforts to unravel the mechanisms that allow a genetic variant (distal-QTL) to confer its effect at distant regions through long-range interactions. By measuring allele-specific biases of various molecular phenotypes occurring along chromatin interactions, I propose two models that intend to explain the propagation of this signal. In the “touch-and-act model” functionality is transmitted through the physical contact of both anchors, independent of the region inside the loop, while in the “spreading model” the function is propagated along the entire loop resulting in a coordinated activation or repression of the whole local neighbourhood. There is evidence for both models occurring at varying proportions, which are partially explained by transcription factor co-enrichments.\r\nFinally, I present a study on how chromatin accessibility impacts the transcriptome and the proteome in mesenchymal stem cells (MSC) from human donors of multiple ages. I also observed a profound misregulation of chromatin organisation occurring with age, possibly due to a decrease in chromatin-related proteins such as histones, CTCF, CENPB, and lamins, which ultimately affect heterochromatin at centromeres and telomeres contributing to genomic instability. By subtle but significant changes in the transcription factor landscape of young and old MSCs, I observe a bias in the differentiation potential. Additionally, I show a loss of bivalent modifications at enhancer and promoter regions that correlate with DNA methylation changes and that could possibly contribute to a decrease in stemness with age.\r\nIn summary, I describe a novel splicing mechanism mediated by chromatin intragenic interactions, propose models of how distal-QTLs propagate histone marks, and advance the understanding of chromatin accessibility changes occurring with age in stem cells."^^ . "2018" . . . . . . . "Mariana"^^ . "Ruiz Velasco Leyva"^^ . "Mariana Ruiz Velasco Leyva"^^ . . . . . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops (PDF)"^^ . . . "PhD_thesis_Mariana_RuizV.pdf"^^ . . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops (Other)"^^ . . . . . . "preview.jpg"^^ . . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops (Other)"^^ . . . . . . "medium.jpg"^^ . . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops (Other)"^^ . . . . . . "small.jpg"^^ . . . "In silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #25418 \n\nIn silico Investigation of Chromatin Organisation in Splicing, Ageing, and Histone Mark Propagation along DNA-Loops\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .