Grant: Discovery Grants Program - Individual

Acquiring new knowledge about molecular mechanisms that control animal metabolism is the main goal of my research. Environmental signals such as oxygen regulate metabolism by changing the expression of genes with functions in fuel use and energy production. Understanding the mechanistic basis of tolerance to low oxygen environments in fishes is important, as climate change manifests through increased occurrences of aquatic environments low in and even devoid of oxygen (hypoxia or anoxia). This has consequences for fish growth, population survival and distribution. Using hypoxia-tolerant zebrafish (Danio rerio) and goldfish (Carassius auratus), we will investigate the oxygen-responsiveness of specific epigenetic marks and their functional role in adjusting energy metabolism to allow survival under hypoxia. We will focus on the role of microRNA-210, a post-transcriptional regulator of target gene mRNA stability/translation. Following the recent, paradigm-shifting discovery of new epigenetic oxygen sensors directly dependent on cellular oxygen to write or erase transcriptional epigenetic marks, we will also focus on specific epigenetic marks dependent on this process: the histone modifications H3K4me3/H3K27me3 and DNA methylation. Because epigenetic marks can be altered and passed on in somatic and germ cells, they can affect gene expression over long periods of time within- and even between generations. We will first induce different degrees and duration of aquatic hypoxia and anoxia to identify thresholds of induction for hypoxia-responsive epigenetic marks in tissues and gametes. Using CRISPR/Cas9 genome-editing and pharmacological manipulation, we will then focus on the role of the hypoxia-responsive microRNA-210 in conferring organismal hypoxia tolerance through metabolic plasticity within and between generations. To this end, we will assess loss of equilibrium as a sensitive marker of organismal hypoxia tolerance, quantify metabolites, and use newly available genome and epigenome information to measure regulation of bona fide metabolic target genes. Finally, and relevant to environmentally relevant multi-stressor scenarios, we will investigate the role of these hypoxia-sensitive epigenetic marks in crosstalk with a major contaminant detoxification pathway termed the Aryl hydrocarbon receptor pathway. Together, this work will provide novel mechanistic understanding of fish metabolism in the context of hypoxia alone or in conjunction with contaminants. The work has strong potential to identify functional epimarkers of hypoxia exposure, with potential for application in aquaculture and fish conservation. Importantly, young scientists will receive state-of-the art training in fish metabolism, molecular biology/epigenetics and toxicology in a dynamic and inclusive research environment. They will disseminate results through publications and conferences and will be highly sought after by academia, government and industry research departments.