SYSTEMIC AND TRANSGENERATIONAL REGULATION OF GENE EXPRESSION BY SMALL RNAS IN C. ELEGANS
Jose, Antony M
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Development of an organism requires information contained minimally within a single cell. This information is inherited in two forms- the genome sequence and regulatory molecules. Little is understood about the types of the regulatory molecules inherited or the impact of parental experiences on them. However, environmental stimuli can alter gene expression without changing DNA sequence and these changes can be inherited suggesting heritable regulatory molecules are influenced by parental experience. Such changes could require communication of regulatory information between cells within an animal (systemic regulation) and across generations via germ cells (transgenerational regulation). Double- stranded RNA (dsRNA) introduced to an animal can silence a gene of matching sequence within that animal and this silencing can persist in progeny suggesting that RNA has the potential to transfer gene-specific regulatory information. Using RNA silencing in C. elegans, we identify conditions that facilitate systemic and transgenerational regulation of gene expression. Previous work suggested that two forms of dsRNA, short and long, could move between somatic cells to cause systemic silencing. However, we show that the movement of short dsRNA is not an obligatory feature of systemic silencing and that long dsRNA introduced by feeding likely enters every cell to cause silencing. Silencing by dsRNA can also be communicated to the germ cells, however this does not guarantee persistence of silencing in descendants. Even the same target sequence expressed from different genetic contexts shows varying susceptibility to transgenerational silencing. Most tested genes recover from silencing in a few generations suggestive of mechanisms that repair changes induced in ancestors. We characterize a unique gene that is exceptionally susceptible to transgenerational silencing that lasts for >200 generations and find that non-genomic signals mediate its expression pattern in every generation. A forward genetic screen to isolate mutants exhibiting re-activation of gene expression (Rage) after many generations of silencing revealed additional defects indicative of endogenous processes that utilize transgenerational silencing mechanisms. We speculate that homeostatic mechanisms that prevent or preserve induced changes maintain form and function across generations in living systems.