Imprinted maternally-expressed microRNAs in induced neurons

Imprinted genes with parental-biased allelic expression are enriched in pathways regulating energy homeostasis. Here, we functionally characterize a large cluster of maternally-expressed microRNAs (miRNAs) to explore the molecular and cellular consequences of imprinted miRNA activity in neurons. Using an induced neuron (iN) culture system, we show maternally-expressed miRNAs from the miR-379/410 cluster direct the RNA induced silencing complex (RISC) to transcriptional and developmental regulators, including paternally-expressed transcripts. Maternal deletion of this imprinted miRNA cluster results in increased protein levels of several targets and up-regulation of a broader gene program regulating synaptic transmission and neuronal function. A subset of these transcriptional changes can be attributed to de-repression of Plagl1, a paternally-expressed transcriptional activator that regulates Igf2, a major factor in energy homeostasis. These data suggest non-coding RNAs actively engage as maternally-expressed miRNAs antagonize paternally-driven gene programs in neurons. Overall design: We examined gene expression in hybrid mouse embryonic stem cells (mESCs, Day 0) and induced neurons (iNs, Day 10) upon deletion of maternal miR-379/410 using rRNA-depleted RNA-seq and small RNA-seq. We also performed Ago2 seCLIP-seq in iNs expressing exogenous untagged-Ago2 or HA-Ago2 with HA antibody.