Mammals inherit two copies of each gene—one from their mother and one from their father. In most cases, the gene copy inherited from each parent is functionally indistinguishable. But a subset of genes, known as imprinted genes, are selectively activated from only one parental copy and, thereby, can differentially affect offspring depending on the parent-of-origin. Imprinted genes are most active in the placenta and brain and regulate pathways such as those controlling growth and behavior. Interestingly, the functions of maternally-expressed genes (genes active only on the maternally-inherited copy) frequently oppose the functions of paternally-expressed genes. For example, many paternally-expressed genes enhance embryonic growth whereas maternally-expressed genes conserve maternal resources by repressing growth. A new study, led by Amanda Whipple, reports that a group of maternally-expressed genes may act in additional ways to antagonize paternally-expressed genes in the brain.
Whipple et al. initiated this study by asking questions about a peculiar group of maternally-expressed genes that do not encode for proteins. These genes are known as microRNAs because of their extremely small size. They typically function in the cell by binding to and repressing transcripts with complementary sequence. In other words, they negatively regulate the expression of other genes. Whipple et al. thought that if they could identify the targets of imprinted microRNAs in neurons they may gain insight into why these genes evolved parent-specific expression in the brain. Using a technique called CLIP-seq, they identified a set of putative microRNA targets in neurons. Amongst these targets were factors that regulate transcription and development, including critical regulators of neuron function. Strikingly, they observed an enrichment amongst the microRNA targets for paternally-expressed transcripts. Deletion of this group of microRNAs from the maternally-inherited allele in neurons resulted in increased protein levels of paternally-expressed targets, consistent with their repression by microRNAs. These changes ultimately led to up-regulation of a broader transcriptional program regulating synaptic transmission and neuronal function. To determine the effect of imprinted microRNA activity on neuron function, Whipple et al. performed electrophysiology experiments and found that deletion of the microRNAs resulted in increased synaptic activity. Overall, these data suggest the maternal genome utilizes the microRNA pathway to antagonistically regulate paternally-driven gene programs in neurons.
The evolutionary pressures driving imprinting are openly debated, but evolutionary theories predict interactions amongst imprinted genes, which is supported by experimental findings. This new study suggests that a group of microRNAs, through their coordinated expression, may serve as a master regulator of an imprinted gene network. The Whipple lab continues to explore additional activities of imprinted non-coding RNAs. They hope their studies will reveal novel insights into how which parental gene inheritance affects gene regulation in the brain.