Stewart, SK;
(2015)
DNA hydroxymethylation and methylation dynamics during neural differentiation.
Doctoral thesis , UCL (University College London).
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Abstract
5’-methylcytosine (5mC) plays a crucial role in the epigenetic regulation of gene expression and, until recently, was the only known epigenetic mark to result from the chemical modification of bases in mammalian deoxyribonucleic acid (DNA). The discovery of 5’-hydroxymethylcytosine (5hmC) at physiologically significant levels in a wide range of tissues, particularly those of the central nervous system, suggests that this novel epigenetic modification may have a similarly important function to 5mC in transcriptional regulation. The highest levels of 5hmC have been consistently found in fully differentiated cell types, whilst stem cells seem to be characterised by very low or insignificant levels of 5hmC. It therefore appears that loss of pluripotency is associated with a substantial increase in global 5hmC levels and this modification may play a crucial role in this switch in cell fate. The central aim of this project was to investigate the potential role of 5hmC by profiling both 5mC and 5hmC in parallel during the differentiation of embryonic stem cells (ESCs) down a neural lineage, allowing for a deeper understanding of the potential function of 5hmC in the genome. Analysis of genome-wide 5mC and 5hmC patterns in ESCs, neural stem cells (NSCs) and astrocytes supported the hypothesis that dynamic changes in the distribution of both modifications contribute to neural specification. Striking differences in 5hmC levels between in vitro- and in vivo-derived samples were observed, suggesting that cell culture models may not successfully recapitulate 5hmC profiles observed during normal development. Finally, a novel method was successfully developed and validated for genome-wide 5hmC profiling (oxBS-450K), allowing sensitive and reproducible detection of 5hmC at single-base resolution.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | DNA hydroxymethylation and methylation dynamics during neural differentiation |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Keywords: | DNA methylation, Hydroxymethylation, Epigenetics |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1471997 |
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