Chromatin and metabolic regulation of plasticity in a predatory nematode

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PROJECT SUMMARY: The environment can elicit multiple phenotypes from a single genotype, a phenomenon referred to as developmental (phenotypic) plasticity. Early-life environmental conditions can have lasting consequences on adult health, such as fetal exposure to toxic chemicals or malnutrition. However, we can also use developmental plasticity to our benefit, including learning, adaptive immunity, and the benefits of diet and exercise. Despite the importance of plasticity for reproductive fitness and health, we still lack a mechanistic understanding of how it works. My laboratory seeks to address this gap in knowledge by applying biochemical methods to an organismal model of phenotypic plasticity. Evidence from my work and others points to histone modifications as key intermediaries between diet and phenotype. The central hypothesis of our laboratory is that the metabolic substrates of histone modifications are, in effect, the signaling molecules which relay diet to phenotype. Identifying these pathways is necessary to understand how poor – or overly rich – diets contribute to disease. Historically, plasticity has been studied in non-model organisms with limited molecular tools. In contrast, development in model organisms has traditionally focused on invariant processes in invariant conditions. In my lab, we use an animal model that is both (1) experimentally tractable and (2) exhibits an extreme form of plasticity, to reveal the connections between diet and phenotype. Pristionchus pacificus nematodes express one of two possible mouth forms in adults – omnivore or bacterivore – depending on the dietary conditions they experience as juveniles. In my postdoc, I developed P. pacificus as a model system to explore the role of chromatin in plasticity. This work led to the discovery that histone 4 (H4) acetylation controls mouth-form development. The research in my independent laboratory builds off of this result, and seeks to determine the molecular pathways from diet to metabolism, and from metabolism to gene expression. In the first five years, we will investigate the upstream metabolic signals and downstream mechanisms of gene regulation which determine P. pacificus mouth-form. First, we will determine which metabolic pathways are affected by diets that induce either morph. Second, we will determine how these pathways feed into histone- modifications, hormone levels, or both. Third, we will investigate how H4 acetylation induces transcription of genes that control mouth-form. To address these questions, we combine techniques from chromatin biochemistry with unbiased genome-wide approaches. Our long-term goal is to apply the insight gained from these experiments to prevent, or treat, dietary-influenced diseases in humans such as type-II diabetes, obesity, and heart disease.