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Title: The role of DNA sequence signals in the epigenetic reprogramming of CpG islands during oogenesis and early embryogenesis
Author: Saadeh, Heba
ISNI:       0000 0004 5364 1477
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2014
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The reprogramming of epigenetic marks is a genome-wide process and yet CpG islands escape the overall trend. In addition, not all CpG islands behave in the same way. While the majority of CpG islands resist the de novo DNA methylation establishment in the germ lines, ~1600 CpG islands acquire methylation during oogenesis. The majority of these oocyte-methylated CpG islands remain un-methylated during spermatogenesis, that is, they are maternal germ line differentially methylated regions (maternal gDMRs). All but 25 (permanent) maternal gDMRs lose their methylation post fertilisation and pre-implantation. The DNA sequences of CpG islands was investigated - in the context of transcription in the oocyte - to identify targeting signals for either establishing and/or maintaining, or altogether escaping DNA methylation during oogenesis and in the pre-implantation embryo. The methylation of CpG islands in the oocyte was found to be significantly associated with transcription through CpG islands, as previously observed. However, the sequences of oocyte-methylated CpG islands do not contain a characteristic DNA sequence motif, and neither do the upstream promoters from which transcription through oocyte-methylated CpG islands originates. An analogous de novo motif search successfully identifies TGCCGC, the recognition site of the Zfp57/Kap1 imprint maintenance complex, as a DNA sequence motif that is characteristic for PPM-DMRs. Analysis of the incidence of TGCCGC indicates that not just its presence but also multiple occurrences within a sequence may be required for imprint maintenance. Furthermore, the lack of additional characteristic motifs suggests the absence of additional DNA-binding factors that specifically interact with PPM-DMRs. A period of 8-10bp in the spacing of CpGs in PPM-DMRs was previously observed and proposed as a targeting signal for de novo methylation in the germ line. This observation was reproduced, and the property of the average was found to be representative to only less than the half of the PPM-DMRs. Moreover, the pairs of CpGs 8-10bp apart are in fact depleted in oocyte-methylated CpG islands, consistent with the consequence of accidental deamination over time. The absence of a DNA sequence motif or CpG spacing characteristic of oocyte-methylated CpG islands (including PPM-DMRs) supports a sequence-independent model of de novo methylation establishment during oogenesis. However, the CpG islands that escape this mechanism contain a characteristic CGrich motif that is highly similar to the recognition site of E2F1/2, DNA-binding protein involved in chromatin remodelling that is expressed in oocytes. Logistic-linear regression analyses indicate that the presence of the motif independently conveys significant protection from methylation, regardless of, for example, whether the CpG island is an active promoter. Therefore, the following is proposed: E2F1/2 are part of a mechanism for the active protection of specific CpG islands from de novo methylation in the oocyte.
Supervisor: Schulz, Reiner Sebastian David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available