DNA methylation and non-coding gene regulatory variation in evolution, development and disease
Research in the Hodges Lab strives to understand how epigenetic features shape human genomes. Our work aims to dissect the relationship between DNA methylation and gene regulation, particularly with respect to the gene regulatory activity of non-coding functional elements. We study this relationship on two levels; first, we are interested in how DNA methylation states are established in differentiating cells. Second, we are interested in the relationship between genotype and DNA methylation state (epitype).
Epigenetics, Gene Regulation, DNA methylation, Cancer, Chromatin, Genetics, Functional Genomics
I. DNA methylation of functional elements in differentiating cells
Cis-regulatory elements such as enhancers are docking sites for transcription factors that control gene expression. They are the nodes of complex gene interaction networks that direct cell fate specification and maintain tissue homeostasis. Furthermore, they are believed to be a driving force behind the diversification of organisms. We have shown that cell-type specific regions of intergenic and intronic hypomethylation (iHMRs) identify diverse classes of non-coding regulatory elements, including enhancers. These cell-type specific iHMRs progressively lose DNA methylation during cell fate specification. This process is accompanied by increased DNase hypersensitivity, post-translational modification of histones associated with active transcription, as well as the production of non-coding transcripts (eRNAs) within the enhancer element itself. In embryonic stem cells, many pre-established DHS regions remain methylated, suggesting that enhancer activation is sequential and DNA demethylation is secondary to chromatin remodeling. The order of these activities during differentiation is not well understood. Projects in our lab address these questions utilizing innovative biochemical, functional genomic and bioinformatic approaches.
II. Human methylation variation and disease susceptibility
Enhancers display higher DNA methylation variability between species and human individuals than other genomic elements. These differential patterns of enhancer methylation may reflect individual differences in gene regulation and disease susceptibility. Central to this observation is the proposition that genotype and methylation state are strongly linked, and methylation changes that accompany genetic modifications could be used to infer the status of the enhancer. Understanding the genetic determinants that promote cell-type specific iHMR establishment will therefore be vital to interpreting how changes in changes in DNA methylation patterns result in gene expression differences. Therefore, projects in our lab aim to investigate the interplay between sequence plasticity and methylation state, and to test the functional impact of this variation on gene regulatory activity.