Genomic imprinting is an epigenetic phenomenon that establishes monoallelic, parent-of-origin gene expression. The brain is enriched for expression of imprinted genes compared to most other adult tissues. Imprinted genes expressed in the brain have been shown to function in various aspects of neural development and neurophysiology, including synaptic transmission, learning, and behavior (reviewed in Perez et al. Annu Rev Neurosci, 2016).

Our lab is interested in understanding the functions of imprinted, non-coding RNAs expressed in the brain. Notably, long non-coding RNAs originating from differentially methylated regions regulate the monoallelic expression of several imprinted genes, and can be targeted for disease therapeutics. For example, we previously demonstrated that reduction of the Ube3a-ATS long non-coding RNA restores Ube3a expression in Angelman syndrome by unsilencing the repressed paternal allele in neurons (Meng et al. Nature, 2015). This study serves as a paradigm for how fundamental discoveries of long non-coding RNA regulation can be traslated to novel therapeutic strategies for imprinted disorders. We seek to expand on this work by (1) elucidating the molecular mechanisms by which long non-coding RNAs execute their repressive activities, (2) determining the function of previously uncharacterized long non-coding RNAs, and (3) exploring additional therapeutic opportunities for imprinted disorders.

Beyond cis-acting long non-coding RNAs, imprinted regions contain trans-acting microRNAs and small nucleolar RNAs with brain-enriched expression. We are actively exploring the function of these imprinted transcripts to better understand how parental gene inheritance affects post-transcriptional gene regulation and RNA modifications in neurons. As part of this effort, we have established an in vitro system that allows for deep mechanistic interrogation of imprinted, non-coding RNAs. We will then complement these efforts with in vivo examination of the physiological role of imprinted, non-coding RNAs during normal and dysregulated neurodevelopment.

In vitro differentiation of mouse embryonic stem cells to excitatory glutamatergic neurons by Ngn2 induction