RT Journal Article
SR Electronic
T1 Chronic hypoxia regulates Cytoplasmic Polyadenylation Element Binding Protein 2 alternative splicing to promote HIF1a translation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.05.325290
DO 10.1101/2020.10.05.325290
A1 Emily M. Mayo
A1 Shaun C. Stevens
A1 Anika N. Ali
A1 Christina J. Moss
A1 Sean P. Lund
A1 Gina S. Nazario-Muñoz
A1 Jennifer B. Permuth
A1 Sandy D. Westerheide
A1 Charles E. Chalfant
A1 Margaret A. Park
YR 2021
UL http://biorxiv.org/content/early/2021/07/19/2020.10.05.325290.abstract
AB HIF1 (Hypoxia-inducible Factor 1) is a transcription factor that plays a crucial role in the hypoxia stress response. However, chronic hypoxia exposure can cause irreversible physiological changes that can lead to pulmonary hypertension (PH), and the need for therapeutics to ameliorate these conditions is great and unmet. Previous studies in our lab have demonstrated that CPEB2 (cytoplasmic polyadenylation element binding protein 2) is a translational repressor of one of the HIF1 subunits: HIF1α. Our lab demonstrated that the alternatively spliced CPEB2A isoform of CPEB2 is a repressor of translation, while the CPEB2B isoform is a translational activator of HIF1α during hypoxia, suggesting a major regulatory role for CPEB2 AS in the pulmonary hypoxic response. Although it is well established that during hypoxia, HIF1α levels are dramatically upregulated due to a decrease in the degradation of this factor, we propose that during chronic hypoxia, the expression of HIF1α is maintained via a translational mechanism, likely alongside a decrease in proteolytic degradation. In this study we demonstrate that depletion of the CPEB2B splice isoform has an inhibitory effect on the translation of nascent HIF1α protein during chronic hypoxia, but not the acute phase. We further demonstrate this pathway is dependent on the initiation factor eIF3H. Finally, we show data that indicate CPEB2A and CPEB2B bind differentially to cytoplasmic polyadenylation element consensus sequences depending on the surrounding sequence context. These findings are important since they provide evidence for the potential of CPEB2 to act as a therapeutic target for treating chronic hypoxia-related pulmonary diseases.Competing Interest StatementThe authors have declared no competing interest.