Recent discoveries in the field of epigenetics (the study of heritable changes in gene expression that occur without changing the letters of the DNA alphabet) show that how a cell "reads" those letters is critical to the final phenotype of the cell and ultimately the organism. Adding molecules such as methyl or hydroxy-methyl groups to the backbone of DNA can change how genes interact with the machinery that transcribes the genome, providing cells with an additional tool to fine-tune gene expression. The genomes of many higher eukaryotes are peppered with such modifications.
My group is interested in understanding the roles of genetic and epigenetic processes in cell function during normal development and stress conditions in plants and people. By understanding how the genome and epigenome communicate with one another, we hope to untangle the complexity of gene regulatory processes that underlie both normal development and disease in plants and humans.
Traditionally, phenotype has been defined by a combination of genetic and environmental interactions. Missing from this equation is an understanding of the impact of epigenetic variation and inheritance on phenotypic diversity. We have pioneered new DNA-sequencing technologies that allow the capture of genome-wide DNA methylation patterns in the plant Arabidopsis thaliana and the charting of the effect of these patterns on the activity of any gene in the genome. Cells employ many enzymes that add methyl groups and chromatin modifications at specific sites, maintain established patterns, or remove undesirable modifications. When we compared normal cells with cells lacking different combinations of these enzymes, we discovered that cells put a lot of effort into keeping certain areas of the genome free of methylation. On the flip side, we found that when a whole class of methylases is inactivated, a different type of methylase steps into the breach. This finding may be relevant for a new class of cancer drugs that work by changing the methylation pattern in tumor cells.
We are also using genome-sequencing techniques to explore the genomes, methylomes, and transcriptomes of thousands of A. thaliana accessions to better understand the interplay and impact of genetic, epigenetic, and environmental variation on phenotype. In parallel, we have been exploring how DNA methylation affects the development of human embryonic stem cells, as well as induced pluripotent stem cells, as they are induced to differentiate into other types of cells. How epigenomic dynamics affect a stem cell's capacity to self-renew and how epigenetic factors contribute to the development of tumors and abnormal disease states are poorly understood. We developed a whole-methylome-sequencing method, called MethylC-Seq to explore these dynamics. Using this method, we found numerous large "reprogramming errors" that were previously undetected.
Current approaches to measure epigenomic changes require hundreds to thousands, even millions, of cells, resulting in measurements that constitute an average signal from a large number of cell types with potentially different epigenetic states. Our future efforts will be focused on understanding the epigenomes of individual cells. With few exceptions, such as cells containing polytene chromosomes, studies of the epigenome in individual cells are not yet possible. Our ability to capture and analyze genome-wide base-resolution epigenomic data from individual cells during normal development will dramatically advance our understanding of these important regulatory processes on a genome-wide scale. Understanding the dynamics of the epigenome and its many roles in cell functions will greatly extend our knowledge about the relationship of genotype to phenotype and have wide relevance in understanding healthy and disease states in plants and people.
Grants from The Gordon and Betty Moore Foundation, the National Science Foundation, the Department of Energy, National Institutes of Health, and the W. M. Keck Foundation have provided partial support for these projects.
As of April 14, 2016