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Dr Gavin Kelsey

Abstract:

Title: Understanding the DNA methylation landscape of gametes. 

The mammalian oocyte provides a powerful model for understanding how DNA methylation patterns are established: uniquely, a whole methylation landscape is laid down from scratch in a non-dividing cell.  Moreover, DNA methylation in the oocyte has an essential influence on gene expression after fertilisation in the embryo and potentially throughout life, as in the case of imprinted genes, so understanding the mechanistic principles of methylation and potential causes of errors resulting from environmental factors or assisted reproduction is important for human health.  On the basis of epigenomic profiling in oocytes and genetic experiments, we have derived a model that identifies transcription as a major determinant of the oocyte methylation landscape.  To test this model, we will address the following questions.  How do the transcription and chromatin landscapes evolve during oocyte growth?  What histone modifiers are required to create a chromatin landscape permissive for DNA methylation, and what is their relationship with the transcription machinery?  How does the DNA methylation complex read permissive histone marks?  These questions will be addressed through a combination of cutting-edge genetic approaches, for example, generating modified versions of DNA methyltransferases and histone modifiers, and epigenetic approaches, including methods for single-cell profiling of DNA methylation and visualisation of histone modifications at single loci in single cells.  With the development of single-cell profiling methods, we expect to apply some of the insights gained to mammals other than the laboratory mouse.

References:

  1. Chotalia et al. (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes & Dev. 23, 105-117.  
  2. Smallwood et al. (2011) Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat. Genetics 43, 811–814.  
  3. Tomizawa et al. (2012) DNA methylation establishment during oocyte growth: mechanisms and significance. Int. J. Dev. Biol. 56, 867-875.