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Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome

Köhler, Florian

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Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder characterized by the onset of some age-related phenotypes including arthritis, lipodystrophy and atherosclerosis at a very early age. Cells from HGPS patients express a mutant version of the nuclear envelope component Lamin A (termed Progerin) and have previously been reported to exhibit characteristic histone modification changes. However, how these alterations affect the landscape of chromatin accessibility and global DNA methylation patterns or whether they are linked to disease-specific gene expression changes, is still unknown. In this work, HGPS-specific epigenetic changes were analyzed in primary dermal fibroblasts using ‘Assay for Transposase-Accessible Chromatin using Sequencing’ (ATAC-seq), DNA methylation profiling and ‘DNA Adenine Methyltransferase Identification using Sequencing’ (Dam ID-seq). Importantly, HGPS cells exhibited chromatin accessibility and DNA methylation alterations enriched in lamina-associated domains (LADs). Strikingly, the epigenetic deregulation of LADs corresponded to changes in the Lamin A-associated LAD landscape in HGPS fibroblasts, thus yielding a mechanistic explanation for the observed dynamics. By integrating RNA-sequencing data into the analysis, both the epigenetic deregulation of LADs and the HGPS-specific changes in the LAD interactome were found to contribute to the pathological gene expression signature of patient fibroblasts. Independently of this, HGPS patients could be stratified into two subgroups based on their DNA methylation profiles, with one subgroup revealing an average epigenetic age acceleration of ∼ 10 years. This confirms that at least in a subset of HGPS patients, characteristics of an advanced age are also manifested at the epigenetic level. Taken together, the findings made herein identify the epigenetic deregulation of LADs as a critical and previously unrecognized feature of HGPS that is associated with disease-related gene expression patterns. Hence, they not only add a novel layer to the study of epigenetic changes in the progeroid disease but also significantly advance our understanding of its molecular pathology.

Item Type: Dissertation
Supervisor: Lyko, Prof. Dr. Frank
Place of Publication: Heidelberg
Date of thesis defense: 10 October 2019
Date Deposited: 22 Oct 2019 12:17
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
610 Medical sciences Medicine
Controlled Keywords: Epigenetics, Aging, Hutchinson-Gilford Progeria Syndrome, DNA methylation, Chromatin accessibility, Lamina-associated domains
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