Splicing regulation of alternative exon 23a of the neurofibromatosis type 1 pre‐mRNA by DBIRD complex (560.5)

Hu proteins are neuron‐enriched RNA‐binding proteins that regulate alternative splicing by binding to AU‐rich sequences of pre‐mRNAs. Recently, we showed that Hu proteins participate in epigenetic regulation of the Neurofibromatosis type 1 (NF1) exon 23a splicing by directly interacting with HDAC2 and inhibiting its deacetylation activity to induce local histone hyperacetylation surrounding exon 23a, leading to increased local transcriptional elongation rate and decreased exon inclusion (Zhou et al., PNAS, 2011). DBIRD complex, formed by DBC1 and ZIRD, increases transcriptional elongation rate across A/T‐rich exons, promoting exon skipping. NF1 exon 23a was identified as a potential DBC1‐dependent alternative exon (Close et al., Nature, 2012). Other studies showed that DBC1 is an inhibitor of two deacetylases. These studies prompted us to propose an intriguing hypothesis that, at the NF1 transcription site, DBIRD, interacting with DNA, and Hu proteins, interacting with RNA, act in a cooperative manner to inhibit HDAC activities, leading to increased local transcriptional elongation rate to skip the NF1 exon 23a. We are using biochemical and genetic approaches to test this hypothesis. Our preliminary data showed that Hu proteins interact with DBIRD complex and that DBC1 alone and DBIRD complex significantly change the NF1 exon 23a splicing. We are currently investigating DBIRD‐ and Hu proteins‐mediated epigenetic control of splicing regulation in CNS neurons isolated from mouse brains. Grant Funding Source : NIH and DOD grants to Hua Lou and Vietnam Education Foundation (VEF) support of Hieu Nguyen