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 collaborate 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 and its role 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.
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