PhD defense by Cecilia Elisabet Lövkvist – Niels Bohr Institute - University of Copenhagen

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PhD defense by Cecilia Elisabet Lövkvist

Title: Modeling spatiotemporal dynamics of DNA methylation

Epigenetics explains how cells with identical genetic material can have different gene expression patterns and thereby varying phenotypes. By the definition used in this thesis, a “mark” is considered to be epigenetic, if it affects gene expression, is stable over time, and is inherited upon cell division. The patterns of epigentic marks depend on enzymes that ensure their maintenance and introduction. Using theoretical models, this thesis proposes new mechanisms for how enzymes operate to maintain patterns of epigenetic marks. Through analysis of experimental data this work gives new insight into how epigenetic marks are distributed in the human genome.

In the first part of the thesis, we investigate DNA methylation and maintenance of methylation patterns throughout cell division. We argue that collaborative models, those where the methylation of CpG sites depends on the methylation status of surrounding CpG sites, explain experimental findings rather than the standard model where CpG sites are independent of surrounding CpG sites. Analyses show that a CpG island cannot be bistable in terms of its average methylation level when using the standard model but it can, when using a collaborative model.

Furthermore, to model a CpG island which is typically surrounded by methylated CpG sites, we also need to include collaborative demethylation and assume the collaboration to be limited to CpG sites in the vicinity and that CpG sites further away have lower rates of influencing the sites within the CpG island. We investigate the distribution of CpG sites in the human genome and observe the methylation of clusters of CpG sites to be inversely correlated to the number of CpG sites within the clusters. To incorporate this in a collaborative model we propose that demethylases and methylases act with different spatial ranges where demethylases and methylases act within shorter and longer ranges, respectively.

We also propose another explanation for the observations on methylation of CpG clusters through the link between DNA methylation and histone modifications. Here we try to include the histones into the game more explicitly in another type of model that speaks out the duality of the two aspects.

Using statistical analysis of experimental data, this thesis further explores a link between DNA methylation and nucleosome occupancy. By comparing the patterns on promoters to regions with similar CpG densities we see the effect of gene expression on DNA methylation and nucleosome occupancy. We find nucleosome occupancy to be correlated to gene expression rather than CpG density, whereas DNA methylation is correlated to CpG density, both on promoter regions and on non-promoter regions.

In the final part of the thesis, we investigate the role of DNA methylation in reprogramming. We propose a regulatory network of pluripotency factors and include the methylation status of the CpG sites of the pluripotency factors to incorporate the assumption of reprogramming as a stochastic process.