The epigenetic network mediated by Ehmt1 and its role in neurodevelopment disorders

Wood, Jamie 2024. The epigenetic network mediated by Ehmt1 and its role in neurodevelopment disorders. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Euchromatic Histone Methyltransferase 1 (EHMT1) is an epigenetic regulator, for which mutations are known to cause the neurodevelopmental disorder (NDD), Kleefstra Syndrome (KS). Despite this, the understanding around the etiology of KS, the role of EHMT1 in neurodevelopment and its overlap with other phenotypically similar NDDs remains poor. The work in this project describes the role of EHMT1 in human neuronal development, alongside the implications of its loss in the establishment of KS. The project utilises CRISPR edited induced pluripotent stem cells (iPSCs) to derive human neurons, investigating epigenetic networks, which underscore proper timing and development. Chapter 3 describes the computational analysis of EHMT1 depleted neurons, focusing on the transcriptional implications and underlying epigenetic changes. Computational modelling revealed significant changes in the genetic architecture of derived neurons which were validated in various cell models. Chapter 4 studies the changes in microRNA expression profiles in EHMT1 depleted cells at both pluripotent and neuronal timepoints. Novel prediction pipelines and manipulation tools were developed to predict these changes. Differing microRNAs were affected at each timepoint, impacting on the expression of other epigenetic modifiers central to neurodevelopment. Chapter 5 describes the implications of EHMT1 loss on the timing of neuronal development and maturation. Changes in epigenetic modifiers and brain specific microRNAs significantly altered the timing and progression of neuronal cells, with changes in various maturation markers. Chapter 6 investigates the epigenetic crosstalk that exists between EHMT1 and other epigenetic modifiers. Global changes were identified in neuronal cells, whilst intricate EHMT1 regulated crosstalk was seen at loci specific regions in pluripotent cells. The project presents novel computational and molecular tools, using them to demonstrate the function of EHMT1 in neurodevelopmental timing and progression. The work elucidates the core mechanisms involved in the establishment of Kleefstra syndrome with broader implications for similar neurodevelopmental disorders.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	3 December 2024
Last Modified:	09 Jan 2025 16:22
URI:	https://orca.cardiff.ac.uk/id/eprint/174468

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