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New Roles of DNA Methylation in the Epigenome and Developmental Overgrowth Syndrome


DNA methylation is an epigenetic mark classically described to repress gene expression in a long and stable manner. DNA methylation plays important roles throughout development as well as throughout life where it maintains many tissue-specific genes in the silent state. DNA methylation is also altered in many diseases. Despite recent interest and innovation in measuring genome-wide DNA methylation, its function in the genome and its role in disease is not well understood. In this body of work, I aim to understand DNA methylation’s role in the cell through perturbation of DNA methylation in two separate contexts: normal mouse embryonic stem cells (mESCs) and a mESC-derived neural stem cell (NSC) disease model.

In the first part of my dissertation (Chapter 2), global perturbation of DNA methylation in mESCs are used to address DNA methylation’s relationship with other members of the epigenome, namely histone modifications. Using a series of mESCs with DNA methyltransferases knocked-out and subsequently rescued, I dissect the causal effects of DNA methylation. By measuring how histone modifications and gene expression change with respect to global DNA methylation, I address whether DNA methylation is capable of regulating histone modifications and gene expression in mESCs. I find that genome-wide DNA demethylation alters occupancy of histone modifications in multiple genomic contexts. Most interestingly, global remethylation of the genome reverses changes in histone modification occupancy, indicating causal regulation by DNA methylation.

In the second part of my dissertation (Chapter 3), highly specific perturbations in DNA methylation are made in mESCs and mESC-derived NSCs to understand what role DNA methylation may play in disease pathogenesis. Mutations recently described in the gene DNMT3A cause an overgrowth syndrome associated with intellectual disability named Tatton-Brown Rahman Syndrome (TBRS). Through genome editing, I establish a cellular model for TBRS where the endogenous Dnmt3a gene contains knock-in of individual missense mutations homologous to those found in TBRS patients. Differentiation of TBRS mESCs into NSCs along with measurements of global DNA methylation, gene expression, and histone modifications reveal downstream consequences of several of these mutations. I find that TBRS-associated DNMT3A mutations largely result in loss of methylation at specific DNMT3A targets. Of particular interest are a group of imprinted genes with known roles in growth and intellectual function. Furthermore, specific DNA methylation changes are also found to associate with changes in histone modification in NSCs.

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