Metabolic Programming of Hematopoietic Stem Cell Function by Prenatal Folate

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ABSTRACT The goal of this project is to determine the effect of prenatal folate status on hematopoietic stem cell (HSC) establishment and function. The Developmental Origin of Health and Disease (DOHaD) hypothesis purports that many adult-onset diseases originate during perinatal development. This phenomenon of developmental programming of disease has since been demonstrated to be mediated at least in part by epigenetic changes during development, as these effects also occur trans-generationally. Folic acid is a major nutritional component that regulates cellular methylation and epigenetic patterning during fetal life, and prenatal folate deficiency is independently associated with failure of neural tube closure. Population-wide folic acid fortification is used in many parts of the world for the prevention of neural tube defects (NTDs), as approximately 70% of NTDs are prevented by folate supplementation. We will test the hypothesis that varying prenatal folate status programs risk for adult-onset disease by altering hematopoietic stem cell function and consequent immune trajectory from the developmental stage onwards. In this grant we propose that heterogeneity, function, and output of the adult HSC compartment can be shaped by perturbation during early development. Our previous work on the effects prenatal inflammation on the developing hematopoietic system show evidence that perturbation during early development can influence adult hematopoiesis and immune function. We will then apply this idea to test the effects of varying prenatal folate on hematopoietic establishment. Proliferation, genomic stability, and cell methylation are all processes influenced by folate-mediated OCM and are known to impact HSC establishment and function. We believe that early life alterations in folate-mediated OCM are likely to influence long-term HSC function. The underlying question of how maternal nutrition influences stem cell outcomes is underexplored. Our preliminary data shows that exposure to varying prenatal folate results in alterations in HSC establishment. Additionally, our model of prenatal folate metabolically reprograms HSCs during fetal life that persist into adulthood with altered function. These changes are in part driven by differences in metabolic gene expression. By examining how prenatal folate alters HSC function, we will be one of the first labs to directly identify the effects of maternal nutrition on health consequences by affecting the establishment and function of HSCs. In addition to the research statement contained within, I have developed a training plan that I believe will ensure my success across all aspects of the proposed research plan. The training plan I have developed not only addresses the training needs that are specific to this proposal but also builds on my interests that will give me tools to investigate metabolic programming, integrate “omics” datasets and stitch together multiple fields related to public health. This training plan includes training specific to metabolism and bioinformatic analysis, as well as career development skills such as mentorship focus, writing skills and presentation skills and academic professionalism. All of the research contained in this proposal will take place in the Beaudin Lab at the University of Utah.