Research Projects
Welcome to the Hall lab! We are interested in the epigenetic mechanisms that regulate environmental programming of gene expression. Environmental experiences in utero or early childhood have been linked to various adult diseases in humans, such as metabolic and mental disorders. Although programmed changes in gene expression are hypothesized to occur via epigenetic factors, the mechanisms regulating the establishment and maintenance of these changes until adulthood are largely uncharacterized. Our lab uses the animal model organism C. elegans and a variety of genetic, imaging, bioinformatic, behavioral, and molecular biology techniques to investigate the mechanisms of environmental programming of gene expression and its impact on adult phenotypes.
Background
Our lab uses the animal model system C. elegans to characterize the mechanisms regulating environmental programming of gene expression due to early life stress. After hatching, worms make a critical developmental decision based on the experienced environmental conditions (temperature, food availability, and population density). If conditions are favorable for growth, worms will continue to develop through the four larval stages to become a ‘control’ adult. However, if conditions for growth are unfavorable, worms will enter into the stress-induced dauer diapause stage. Once conditions improve, worms can exit the dauer stage and resume reproductive growth to become a ‘postdauer’ adult. We take advantage of this developmental decision to explore how different environmental conditions can have stress-specific effects on adult phenotypes.
Environmental programming of gene expression
Using transcriptional profiling of control and postdauer adults that experienced either early-life starvation or crowding, we identified ~500 genes that exhibit opposite changes in mRNA levels depending on their environmental history. We have coined this set of genes the “seesaw” genes. The change in mRNA levels for the seesaw genes is dependent upon their expression patterns and function. Germline expressed genes are downregulated in starvation conditions, while somatically expressed genes are upregulated, and vice versa for the crowding conditions. In addition, the CSR-1 endogenous RNAi pathway is required for seesaw gene expression. One of the lines of research in our lab is understanding how the seesaw genes are targeted, the different mechanisms that maintain the cellular memory of gene expression, and how these changes in gene expression result in stress-specific changes in adult behavior and physiology.
Genome-wide chromatin remodeling
We are interested in how the chromatin state is affected by passage through the stress-induced dauer stage. To examine if the chromatin state was the mechanism retaining the cellular memory of early stressful environments, we performed chromatin immunoprecipitation followed by deep sequencing to examine enrichments of common histone modifications associated with euchromatin and heterochromatin genome-wide. While some loci show a correlation between changes in gene expression and changes in the chromatin state, the unexpected result was an overall, genome-wide chromatin state change in postdauer adults that experienced early-life crowding compared to controls. We found that histone modifications associated with active transcription levels are significantly decreased in postdauer adults compared to control adults. We are currently investigating the mechanism of this genome-wide chromatin remodeling event and its consequences.
Phenotypic plasticity in adults
Changes in gene expression between control and postdauer adults could potentially result in changes in behavior and physiology between the two populations. The largest group of genes with significant changes in gene expression are those involved in reproduction pathways. Consistent with the seesaw gene expression changes, we found that postdauer adults that experienced crowding (high pheromone) have significantly more progeny than their control adult counterparts, while postdauers that experienced starvation have fewer progeny. We have determined that the developmental mechanism regulating the change in brood size is modulation of the onset of germline proliferation in larvae, resulting in different numbers of sperm available for self-fertilization. We are currently investigating the moleuclar mechanisms of reproductive plasticity based on environmental experience.
Regulation of environmental programming by endo-siRNAs
One of the goals of our lab is to characterize epigenetic mechanisms that contribute to the establishment and maintenance of gene expression changes due to environmental programming. We have evidence that endogenous small interfering RNA (endo-siRNA) pathways play a role in regulating seesaw gene expression, genome-wide chromatin states, neuronal gene expression, and reproductive plasticity. In addition, we have shown that the siRNA populations differ in control and pheromone-induced postdauer adults. Although RNAi is commonly used as a molecular tool to knock-down gene expression, little is known about how organisms exploit their own siRNA pathways to regulate endogenous gene expression in response to environmental conditions. Our system allows for us investigate gene expression changes regulated by an endo-siRNA environmental programming mechanism.
Regulation of neuronal gene expression
One of the interests in the Hall lab is understanding how neuronal genes can be regulated by environmental programming and the resulting behavioral outcomes. We have shown that the osm-9 TRPV channel gene is downregulated in postdauer hermaphrodite ADL neurons, resulting in altered responses to the pheromone component ascr#3. Avoidance of ascr#3 is an osm-9 dependent and ADL mediated behavior in hermaphrodites. This developmental history-dependent regulation of osm-9 requires the TGF-beta, chromatin remodeling, and NRDE-3 RNAi pathways. We are currently investigating how these pathways interact and the role of the conserved cis-acting PD motif required for osm-9 downregulation.