Imprinted maternally-expressed microRNAs antagonize paternally-driven gene programs in neurons

Abstract

Imprinted genes with parental-biased expression are hypothesized to result from an evolutionary conflict between the parental genomes over procurement of maternal resources. Accordingly, imprinted genes are enriched in pathways regulating nutrient acquisition, energy homeostasis, and growth. Here, we functionally characterize a large cluster of maternally-expressed microRNAs (miRNAs) to explore why they evolved imprinted expression in neurons. Using an induced neuron (iN) culture system, we show maternally-expressed miRNAs from the miR-379/410 cluster repress paternally-expressed genes, including known regulators of energy homeostasis Plagl1 and Peg3. Additional non-imprinted metabolic regulators are also co-targeted by miR-379/410. Maternal deletion of this imprinted miRNA cluster results in de-repression of its targets and up-regulation of a broader gene program regulating feeding behavior and synaptic transmission. These data suggest non-coding RNAs actively engage in parental genomic conflict, whereby maternally-expressed miRNAs antagonize paternally-driven gene programs in neurons.