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Title: KDM2A and KDM2B mediate widespread transcription repression in mouse embryonic stem cells
Author: Turberfield, Anne
ISNI:       0000 0004 7966 2073
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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DNA methylation is widespread in vertebrate genomes, occurring on cytosine residues in the context of CpG dinucleotides. An important exception to this pervasive methylation are CpG islands (CGIs), short regions of CpG rich, non-methylated DNA that are associated with the majority of transcription start sites. CGIs are bound by proteins containing a zinc finger-CXXC (ZF-CXXC) domain, which specifically recognises nonmethylated CpG dinucleotides. These proteins are found in a variety of chromatin modifying complexes, leading to the generation of a distinctive chromatin environment at CGI gene promoters. KDM2A and KDM2B (KDM2A/B) are recruited to CGI throughout the genome via their ZF-CXXC domain, and act as histone H3 lysine 36 (H3K36) demethylases. H3K36 methylation can inhibit transcription initiation, leading to the proposal that KDM2A and KDM2B may contribute to the generation of a transcriptionally permissive chromatin state at CGI-associated gene promoters through local removal of this repressive mark. However, KDM2A/B have been implicated in transcription repression in other contexts. Furthermore, both KDM2A and KDM2B also appear to possess demethylase-independent modes of transcription regulation, including via the short isoforms of these proteins which lack demethylase activity. Therefore, the genome-wide role played by KDM2A/B in regulating gene expression remains unclear. Here I dissect the contribution of KDM2A/B to transcription regulation. I discover that the histone demethylase activity of KDM2A/B contributes little to the regulation of gene expression in mouse embryonic stem cells. In contrast, I find that loss of KDM2A/B from chromatin leads to a widespread increase in transcription, and show that KDM2B plays the predominant role in transcription repression. I demonstrate that the transcription upregulation following loss of KDM2A/B is not accompanied by changes in the accessibility of CGI gene promoters. Instead, I identify candidate substrates of the putative E3 ubiquitin ligase activity of KDM2A/B. Altered activity or stability of these substrates might result in transcription deregulation. Together, these observations reveal an unexpected and widespread role for KDM2B in transcriptional repression.
Supervisor: Klose, Robert Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available