RNA-based regulation of gene expression in neurodevelopment and disease

Alternative splicing

Many mammalian genes contain introns, which must be spliced out of the newly synthesized transcripts to produce mature mRNAs. This process is extensively controlled in a cell type- and condition-dependent manner often giving rise to alternative splice forms with distinct protein-coding properties, cellular localization, and stability. We have identified a molecular circuitry dampening the expression of a critical splicing regulator, RNA-binding protein (RBP) PTBP1, in developing neurons and are currently exploring the roles of this and other RBPs in neuronal differentiation. PubMed IDs: 17679093, 21948791, 2266123127134173, 30053257 and 31953406.

Noncoding RNAs

We also have a longstanding interest in biological functions of noncoding RNAs, a diverse group of transcripts lacking protein-coding capacity. Along this line, we have recently identified a cancer-enriched long noncoding RNA (lncRNA), PNCTR, containing UC-rich tandem repeats and sequestering multiple copies of PTBP1 in a membraneless structure called the perinucleolar compartment. We are now investigating biological functions of PNCTR and other repeat-containing lncRNAs in different types of cancer cells and developing neurons. PubMed IDs: 18369137, 26144867, and 30318443.

Technology development

We have recently developed a suite of hybridization-proximity (HyPro) labeling approaches for unbiased discovery of proteins and RNAs associated with a transcript of interest in genetically unperturbed cells. As a proof of principle, we showed that HyPro labeling can identify both known and previously unexplored spatial neighbors lncRNAs localizing to membraneless nuclear compartments. We believe that this technology will help us gain new insights into the structure and functions of the mammalian nucleus. PubMed IDs: 34741808 and 35128480.