EU LIFE Lecture - Histone Chaperones Maintain Cell Fates and Antagonize Reprogramming in C. elegans
Understanding the mechanisms that safeguard cellular identities is key to improving cell fate reprogramming, which is of great biological and medical importance. We are using C. elegans as a model organism to identify factors that act as barriers for cellular reprogramming. C. elegans allows in vivo large-scale genetic screens and around 60% of its genes have human homologs. We previously identified that the histone chaperone LIN-53, homolog of human CAF-1p48, protects germ cells from being directly reprogrammed into neurons (Tursun et al., 2011 Science). In an analogous study, CAF-1 was shown to act as a barrier for cellular reprogramming of mouse embryonic fibroblasts (Cheloufi et al., 2015 Nature). Such striking conservation from worm to mouse implies that reprogramming barriers might be shared among C. elegans and humans. We performed a whole-genome RNAi screen against all 20.000 genes of C. elegans and identified around 160 novel factors that counteract reprogramming of different cells into specific glutamatergic neurons. Testing a number of the newly identified factors in human fibroblasts revealed the essential chromatin regulator FACT (FAcilitates Chromatin Transcription) as an evolutionarily conserved barrier for cell fate reprogramming (Kolundzic et al., in revision).
Additionally, we are studying whether regulation of reprogramming is linked with Aging regulation. Several observations in our lab suggest that reprogramming factors are implicated also in lifespan maintenance suggesting a link between safeguarding cell fates, cellular homeostasis and the control of Aging.
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