HAVE IMAGE OF A BLI-5: Epigenetic Inheritance in a C. elegans Model of Increased Second Generational bli-5 Penetrance

In recent years, an expanding understanding of the field of epigenetics has allowed the scientific community to appreciate the vastly important role epigenetic marks play in defining who we are, from the basic level of what any given cell will differentiate into to overarching traits such as susceptibility to stress or predisposition towards developing autism. While the study of epigenetics has burgeoned, the exploration of certain other biological phenomena has languished. One such phenomenon is that of incomplete penetrance, also known as reduced penetrance, which refers to situations in which a mutant genotype confers its associated mutant phenotype on some, but not all, carrier organisms. For humans, this phenomenon may be couched in terms of risk factors; the BRCA mutations, for example, exhibit incomplete penetrance in humans, with some carriers going on to develop breast, ovarian, prostate, or pancreatic cancers while other carriers live a cancer-free life. The cause of a given trait's incomplete penetrance is likely to depend on many factors, including genetic and environmental interactions. However, our laboratory's research with a C. elegans model of incomplete penetrance caused by mutations in the blister genes, bli-1 through bli-6, has established that genotypically identical worms grown in the same controlled environment still exhibit incomplete penetrance of blister formation, suggesting that factors beyond genetics and the environment are at play. Our observations from the summer of 2013 raise the possibility of a role for epigenetic influences in incomplete penetrance: in a preliminary study, wildtype worms grown on bli-5 RNAi for one generation exhibited a lower blister penetrance than did their progeny, a second generation of worms whose parent worms had spent their entire life on bli-5 RNAi. The two generations of worms were genetically identical, grew to adulthood eating the same bli-5 RNAi and were scored for blisters at the same time period in their life cycle, yet the second generation had increased penetrance of the blister phenotype. This study employed RNAi interactions on N2 wildtype worms to demonstrate that increased second generational penetrance does indeed occur with wildtype worms grown on bli-5 RNAi and that knocking down expression levels of certain genes involved either specifically in the epigenetic inheritance pathway (hrd-1) or in creating epigenetic changes in cuticle progenitor cells (hda-4) attenuates this phenomenon. Additionally, transcriptional and translational reporter genes for bli-5 expression were created