Programs & laboratories : Laboratory of Translational RNA Genomics


We are primarily interested in transcriptomic and epigenetic mechanisms of gene regulation in the central nervous system development and disease, and in particular in the emerging roles of long noncoding RNAs (lncRNAs). In order to comprehensively study molecular processes underlying neural development and disease, we apply a variety of high-throughput genomics techniques including RNA sequencing (RNA-seq), and bisulfite sequencing to assess DNA methylation, in addition to a range of molecular and cell biology techniques. We utilize these techniques to characterize changes in post-mortem brain tissues from patients with disorders of the CNS. In addition, we have established an in vitro system of primary human neural stem cells that we use to model processes of differentiation of neural cells, in particular astrocytes. Using these techniques and models, we have identified a number of Natural Antisense Transcripts associated with Alzheimer’s disease and autism and regulating processes of neural development.
Natural Antisense Transcripts (NATs) are a class of lncRNA molecules that are transcribed from the opposite DNA strand of other RNA transcripts. Of the proposed functional mechanisms of NATs, regulation of chromatin architecture and epigenetic memory have received much attention as antisense transcripts can provide a scaffold by which proteins can interact with DNA and chromatin in a locus specific manner.
Recently, we have shown that some NATs can epigenetically modify gene expression in cis, making them unexplored targets to achieve specific upregulation of gene expression. Specifically, we have shown that brain-derived neurotrophic factor (BDNF) is under the epigenetic control of an antisense transcript, BDNF-AS. Depletion of BDNF-AS can alter chromatin marks at the BDNF locus and upregulate locus-specific gene expression both in vitro and in vivo. Our study also described NAT-mediated suppression of other genes such as glial-derived neurotrophic factor (GDNF) and ephrin type-B receptor 2 (EPHB2), suggesting that antisense RNA-mediated transcriptional suppression is a frequent phenomenon. Our breakthrough findings have shown the possibility that endogenous gene expression can be specifically upregulated in vivo by targeting NATs.
More recently, we have identified a number of NATs expressed from genomic loci associated with autism disorder. We showed that these NATs are differentially expressed in regions of the human brain, suggesting their role in brain patterning. Particularly, antisense RNA to SYNGAP1 (SYNPAG1-AS), was upregulated in the cortex of autism patients, implying that this NAT plays a functional role in autism.
Current projects in the lab include studying roles of long noncoding RNAs in autism and differentiation of astrocytes, molecular mechanisms of noncoding RNA-protein interactions and potential novel therapeutic approaches to Alzheimer’s disease treatment by targeting epigenetic proteins. We are also developing bioinformatics tools and software suits to facilitate analysis of next-generation sequencing data and noncoding RNA annotation.