TY - BOOK

T1 - Modeling spatiotemporal dynamics of DNA methylation

AU - Lövkvist, Cecilia Elisabet

PY - 2017

Y1 - 2017

N2 - Epigenetics explains how cells with identical genetic material can have different gene expressionpatterns 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 inheritedupon cell division. The patterns of epigentic marks depend on enzymes that ensure theirmaintenance and introduction. Using theoretical models, this thesis proposes new mechanismsfor how enzymes operate to maintain patterns of epigenetic marks. Through analysis of experimentaldata this work gives new insight into how epigenetic marks are distributed in thehuman genome.In the first part of the thesis, we investigate DNA methylation and maintenance of methylationpatterns throughout cell division. We argue that collaborative models, those where themethylation of CpG sites depends on the methylation status of surrounding CpG sites, explainexperimental findings rather than the standard model where CpG sites are independent ofsurrounding CpG sites. Analyses show that a CpG island cannot be bistable in terms of its averagemethylation level when using the standard model but it can, when using a collaborativemodel.Furthermore, to model a CpG island which is typically surrounded by methylated CpGsites, we also need to include collaborative demethylation and assume the collaboration to belimited to CpG sites in the vicinity and that CpG sites further away collaborate have lowerrates of influencing the sites within the CpG island.We investigate the distribution of CpG sites in the human genome and observe the methylationof clusters of CpG sites to be inversely correlated to the number of CpG sites withinthe clusters. To incorporate this in a collaborative model we propose that demethylases andmethylases act with different spatial ranges where demethylases and methylases act withinshorter and longer ranges, respectively.We also propose another explanation for the observations on methylation of CpG clustersthrough the link between DNA methylation and histone modifications. Here we try to includethe histones into the game more explicitly in another type of model that speaks out the dualityof the two aspects.Using statistical analysis of experimental data, this thesis further explores a link betweenDNA methylation and nucleosome occupancy. By comparing the patterns on promoters toregions with similar CpG densities we see the effect of gene expression on DNA methylationand nucleosome occupancy. We find nucleosome occupancy to be correlated to gene expressionrather than CpG density, whereas DNA methylation is correlated to CpG density, both onpromoter regions and on non-promoter regions.In the final part of the thesis, we investigate the role of DNA methylation and its role inreprogramming. We propose a regulatory network of pluripotency factors and include themethylation status of the CpG sites of the pluripotency factors to incorporate the assumptionof reprogramming as a stochastic process.iii

AB - Epigenetics explains how cells with identical genetic material can have different gene expressionpatterns 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 inheritedupon cell division. The patterns of epigentic marks depend on enzymes that ensure theirmaintenance and introduction. Using theoretical models, this thesis proposes new mechanismsfor how enzymes operate to maintain patterns of epigenetic marks. Through analysis of experimentaldata this work gives new insight into how epigenetic marks are distributed in thehuman genome.In the first part of the thesis, we investigate DNA methylation and maintenance of methylationpatterns throughout cell division. We argue that collaborative models, those where themethylation of CpG sites depends on the methylation status of surrounding CpG sites, explainexperimental findings rather than the standard model where CpG sites are independent ofsurrounding CpG sites. Analyses show that a CpG island cannot be bistable in terms of its averagemethylation level when using the standard model but it can, when using a collaborativemodel.Furthermore, to model a CpG island which is typically surrounded by methylated CpGsites, we also need to include collaborative demethylation and assume the collaboration to belimited to CpG sites in the vicinity and that CpG sites further away collaborate have lowerrates of influencing the sites within the CpG island.We investigate the distribution of CpG sites in the human genome and observe the methylationof clusters of CpG sites to be inversely correlated to the number of CpG sites withinthe clusters. To incorporate this in a collaborative model we propose that demethylases andmethylases act with different spatial ranges where demethylases and methylases act withinshorter and longer ranges, respectively.We also propose another explanation for the observations on methylation of CpG clustersthrough the link between DNA methylation and histone modifications. Here we try to includethe histones into the game more explicitly in another type of model that speaks out the dualityof the two aspects.Using statistical analysis of experimental data, this thesis further explores a link betweenDNA methylation and nucleosome occupancy. By comparing the patterns on promoters toregions with similar CpG densities we see the effect of gene expression on DNA methylationand nucleosome occupancy. We find nucleosome occupancy to be correlated to gene expressionrather than CpG density, whereas DNA methylation is correlated to CpG density, both onpromoter regions and on non-promoter regions.In the final part of the thesis, we investigate the role of DNA methylation and its role inreprogramming. We propose a regulatory network of pluripotency factors and include themethylation status of the CpG sites of the pluripotency factors to incorporate the assumptionof reprogramming as a stochastic process.iii

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/fbp0ps/alma99122333858505763

M3 - Ph.D. thesis

BT - Modeling spatiotemporal dynamics of DNA methylation

PB - The Niels Bohr Institute, Faculty of Science, University of Copenhagen

ER -