Research in the Richards lab is broadly focused on epigenetics, the study of inherited information superimposed on the genetic sequence. Most of our efforts to date have concentrated on cytosine methylation, which is one of the most fundamental types of epigenetic information in eukaryotic cells. We are interested in both the regulation of cytosine methylation and the phenotypic consequences of variation in cytosine methylation patterns. Our work also extends to higher-order epigenetic information encoded in alternative chromatin packaging and the three-dimensional organization of the genetic material. Our studies take advantage of the genetic and genomic resources available in the model organism Arabidopsis thaliana.
Chromatin - DNA Methylation Interface
Our forward genetic screens for Arabidopsis variants with reduced cytosine methylation levels have led to two unexpected gene targets that encode proteins implicated in chromatin regulation. These findings underscore the interconnections between chromatin and DNA modification. The first gene discovered in our genetic screens, DDM1 (DECREASED DNA METHYLATION 1), encodes a SNF2 family nucleosome remodeling protein. Loss of DDM1 function leads to dramatic loss of cytosine methylation in heterochromatic repeats as well as a loss of histone modification marks characteristic of heterochromatin. Mammalian DDM1 orthologs appear to play an analogous role in the maintenance of heterochromatic epigenetic markers. How DDM1 facilitates deposition and retention of heterochromatic marks is poorly understood and one objective of our research program is to elucidate these mechanisms.
The second class of chromatin proteins uncovered by our genetic screens binds methylated cytosine residues via an SRA (SET- and RING-associated) domain. We are focusing on the VIM (VARIANT IN METHYLATION) protein family, a subclass of SRA domain methylcytosine-binding proteins required for maintenance of CpG methylation throughout the genome. Our goal is to understand how these proteins interpret cytosine methylation patterns and coordinate epigenetic regulation across the DNA methylation-chromatin interface.
Epigenetic Variation and Inheritance
In our initial characterization of Arabidopsis mutations that reduce DNA methylation we observed that the hypomethylated state of different genomic regions was inherited through meiosis independently of the mutations that caused the aberrant methylation. This simple genetic result led us to undertake a variety of studies to weigh the interaction between genetic and epigenetic variation. This work, in turn, has sparked a broader investigation of the prevalence and significance of epigenetic variation in plants within an agricultural, ecological, and evolutionary context.
Nuclear Architecture
The three-dimensional organization of eukaryotic nuclei is an important topic of study from both a cell biological and an epigenetic perspective. The determinants that specify nuclear architecture can affect the epigenetic state of different genomic compartments. We are striving to bridge our understanding of epigenetic codes at the level of DNA and chromatin modification with higher-order epigenetic information embedded in three-dimensional nuclear organization. We are beginning this long-term effort with a project centered around a group of nuclear coiled-coil proteins that we have called LINC (LITTLE NUCLEI) for the reduction in nuclear size and alteration in nuclear shape caused by combining loss-of-function mutations in LINC paralogs. LINC proteins are plant-specific but share some structural features reminiscent of animal lamins, which are the key constituent proteins of the nuclear lamina - a mesh-like cage that underlies the nuclear membrane in animal cells. In our LINC project, we are pursuing two different research questions: the first is aimed at understanding how LINC proteins control plant nuclear architecture, while the second explores the interaction between nuclear organization and epigenetics.
Everyone knows by now that excessive exposure to the sun’s radiation can cause skin cells to become cancerous. Cancer occurs because radiation causes changes (mutations) in the cell’s DNA sequence. But cancer and other diseases can also occur when certain genes that might have protected the cell are “silenced” or turned off. In this case, the protective genes become unreadable by the cell and disease can result. Understanding how these genes become “unreadable” is the goal of a relatively new area of genetics research called epigenetics.
Eric Richards’ laboratory studies epigenetics in the model plant Arabidopsis. “Epi-“ means “on top of” or “in addition to,” so epigenetic traits exist on top of or in addition to the cell’s DNA sequence. Epigenetics research seeks to understand the molecular mechanisms that change the information contained in the DNA (making it unreadable) without changing the underlying DNA sequence. Richards focuses on one of these mechanisms, called “DNA methylation.” In this process, a small chemical group is added to one of the DNA bases (cytosine) which can make the gene unreadable by the cell. The methylated gene can die out with the cell or it can be passed on to new generations of cells and, in some cases, organisms. Consequently, DNA methylation may play an important role in evolution, just as mutations do.
Richards is working to understand how, where and when DNA methylation occurs, its consequences on the organism, and to what extent variation in methylation is passed on to future generations. He is studying this process in plants because they can survive major epigenetic alternations that other organisms, like mice, cannot.
Understanding the basic biology of DNA methylation in plants could have applications to human health, such as the detection and prevention of disease. But it also has important applications in agriculture. Epigenetics controls important traits in crop plants, such as disease resistance and flowering time, so advances in this field of genetics could lead to higher quality food or increased yields.
