Abstract 18212: Unique Exonic RNA Polymerase II Pausing in the Hypoxia Inducible Factor-1 Alpha Gene is Associated With Alternative Splicing

Hypoxia-inducible factor 1α (Hif-1α) is the primary transcription factor that promptly increases upon exposure of the cells to hypoxia. It is mainly regulated by posttranscriptional and posttranslational mechanisms involving miR-199a and prolyl hydroxylase, respectively. In addition, the discovery of multiple Hif-1α isoforms suggests that alternative splicing may play a role in regulating its activity, although little is known about this in the heart. We, thus, hypothesized, that in addition to the known mechanisms, Hif-1α is activated by an alternative splicing step, a process that is tightly coupled to transcription. To test this, we treated myocytes with antimiR-199a, which robustly induces Hif-1α expression, and analyzed its effects on gene transcription using RNA polymerase II Chromatin immunoprecipitation-deep sequencing. The analysis revealed that antimiR-199a induced 1) the upregulation of genes that are predominantly Hif-1α targets including Pdk1, Glut3, Vegfa, Bnip3, Ndrg1, and Gys1, in addition...