Cell Fate Safeguarding by the Mitochondrial Dehydrogenase IDH3 via linked Metabolism and Epigenetic Pathways in C. elegans.

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Prospective tissue replacement therapies require specific cell types to replenish and repair diseased organs of patients. For instance, healthy neuronal cells could regenerate brain tissues of Alzheimer’s patients. One promising source for new healthy cells is to convert the identity of abundantly available cells such as astrocytes or fibroblasts. Cell type conversion is achieved by reprogramming, which requires overexpression of specific transcription factors. However, transcription factors are usually restricted in their efficiency to induce reprogramming due to cell fate safeguarding mechanisms. While much is known about how cell fates are specified during development, cellular maintenance and safeguarding mechanisms are not fully understood. This, however, is essential to improve cellular reprogramming for future regenerative medicine applications. We previously demonstrated that the nematode C. elegans is a powerful model organism to identify evolutionarily conserved safeguarding mechanisms of cells (Müthel et al., 2019 AgingCell; Hajduskova et al., 2019 Genetics; Kolundzic et al., 2018 DevCell; Seelk et al., 2016 eLife; Tursun et al., 2011 Science). Using reverse genetics, we now identified the conserved mitochondrial isocitrate dehydrogenase IDH3 as a barrier for reprogramming germ cells into neurons. This unexpected barrier is critical for metabolism, raising the question of how perturbations in mitochondria create permissiveness for cell fate conversion. Our preliminary results indicate that IDH3 depletion causes impaired gene expression regulation by decreasing repressive chromatin. Yet, how signaling pathways integrate metabolic states to elicit epigenetic changes is not well understood. This research proposal aims at deciphering molecular pathways, which link metabolism and epigenetics to maintain cell states and counteract reprogramming. To elucidate relevant molecular processes, we are combining genetics, cell-specific transcriptomics (RNA-Seq), and chromatin accessibility assays (ATAC-Seq) with spectrometry-based analysis of metabolites. Strikingly, we also encountered non-cell-autonomous effects upon IDH3 depletion, indicating that other tissues contribute to germ cell fate safeguarding. Knowledge about non-cell-autonomous effects is essential for future regenerative medicine as they can have opposing effects in vitro vs. in vivo. Therefore, the use of living animals to study cellular safeguarding and reprogramming can reveal critical cellular and trans-tissue pathways that affect cell fate plasticity in the physiological context of intact tissues. Overall, knowledge about non-cell-autonomous effects of metabolic and epigenetic gene expression regulation is fundamental to improve reprogramming for future tissue replacement applications.