We are please to announce a seminar by Sébastien Smallwood from the Babraham Institute (Cambridge). It will be in the IAB at 2 pm on Thursday, July 23rd 2015.
DNA methylation dynamics during germ cell specification and early embryonic development.
DNA methylation is an epigenetic mark tightly associated to cellular identity by directing dynamic yet stable and heritable regulation of gene expression. The DNA methylation landscape is highly remodeled during germ cell specification and early embryonic development, and the aim of our work is to understand how DNA methylation is established and regulated during these developmental windows.
In this context, we have developed methods combining bisulfite conversion and high-throughput sequencing to determine the genome-wide distribution of DNA methylation from low amount of starting material. This allowed us to unraveled the DNA methylation landscape of mouse oocytes. We identified a large number of CpG islands that are specifically methylated in female germ cells but not related to genomic imprinting. This finding put the emphasis on the role of post-fertilisation maintenance as the key determinant of imprinting. We shown that Dnmt3a and importantly Dnmt3L are both required for DNA methylation targeting in all genomic contexts.
We have performed deep RNA-Seq and transcriptome assembly in growing oocytes. This revealed the existence of many non-annotated transcripts, and the tight correlation between DNA methylation and active transcriptional units. Using genetic approaches we observed a functional link between transcription and DNA methylation targeting, reflecting the capability of Dnmt3a to interact with H3K36me3.
We are now characterising the dynamics of DNA methylation establishment in early embryos (E3.5 => E6.5). We observed (aside from imprinting) significant maternally derived DNA methylation in E3.5 blastocysts, suggesting that the textbook version of epigenetic reprogramming of the maternal genome by passive demethylation was not fully accurate. In addition we detected a high degree of DNA methylation heterogeneity in blastocysts, at the population level. To investigate this in more detail, we have developed a new method allowing for the first time the measure of DNA methylation, genome-wide, from single cells (scBS-Seq) and we are assessing whether DNA methylation heterogeneity could influence early cell fate decisions.