I have had a long-standing interest in studying RNA regulatory mechanisms in development. My lab has focused on studying the mechanism of action of Evfs, novel long non-coding RNAs that regulate transcription factors essential for proper GABAergic interneuron development. Although a critical role for developmentally regulated transcription factors in patterning and differentiation has been established for some time, the role of long non-coding RNAs (lncRNAs) is only beginning to be understood. With genome-wide sequencing technologies, it is now known that the majority of transcripts are non-coding, (ie do not code for proteins). My lab's work on Evf2 has established some fundamental principles regarding lncRNA transcriptional regulation. Evf2 is conserved across vertebrates (ultraconserved), and is a sonic hedgehog target in the developing forebrain. We showed that Evf2 is transcribed across an enhancer, retaining enhancer sequences in the spliced mature transcript, complexing with the Dlx2 homeodomain transcription factor, and regulating Dlx 5/6 enhancer activity (Feng et al. 2006). Through analysis of an Evf2 loss-of-function mouse model developed in my lab, we reported that the Evf2ncRNA is required for proper regulation of genes in the Dlx 5/6 region, and adult hippocampal circuitry (Bond et al. 2009). We proposed a novel mechanism in which a DNA regulatory element is regulated by a complementary lncRNA critical for gene regulation in developing interneurons. More recently, we identified that Evf2 recruits both activator and repressor to the Dlx5/6 enhancers, repressing site-specific methylation (Berghoff et al, 2013), and forming a large ribonucleoprotein complex (Evf2, Cajigas et al. 2015). Future work will define the role of Evf2-RNP interactions in gene regulation in interneurons.

We have recently been funded by the NIMH to study how long noncoding RNAs regulate enhancer-chromosomal interactions across megabase distances. We are addressing the biological significance of these RNA-mediated chromosomal interactions during interneuron development.