Over the last two decades it has become clear that epigenetic modifications acquired by an individual during its lifetime can be inherited for multiple generations. We have developed a transgenerational epigenetic inheritance sensor in the model organism Caenorhabditis elegans in which RNAi-induced silencing of a GFP transgene is robustly inherited for multiple generations.
Using this model, we identified a network of proteins involved in epigenetic inheritance, classifying them into three groups: those involved in establishment, maintenance, or both. This distinction has implications for how epigenetic signals are maintained not only in the context of transgenerational epigenetic inheritance, but in epigenetic memory throughout development as well.
Most of the proteins we identified have homologs in mammals and two of particular interest are SET-9 and SET-26, homologs of KMT2E/MLL5. Although poorly studied, KMT2E/MLL5 has been implicated in many diseases including cancer, immune regulation and autism, and was recently identified as the cause of O’Donnell-Luria-Rodan (ODLURO) syndrome. Symptoms of ODLURO syndrome include global development delay, ASD and epilepsy. We have shown that SET-9 and SET-26 are defective in epigenetic inheritance and show progressive sterility. SET-9 and SET-26 bind H3K4me3 with high affinity in vitro. Mutation of SET-9 and SET-26 causes widespread disruption of H3K4me3, leading to activation of genes that should be silenced. We hypothesise that this disruption to the global epigenome when KMT2E/MLL5 is mutated in humans causes ODLURO syndrome, and leads to the development of cancer.