Intermittent hypoxia regulates RNA polymerase II in hippocampus and prefrontal cortex.
Intermittent hypoxia (IH) is a major pathological factor in the development of neural deficits associated with sleep-disordered breathing. Here we demonstrate that IH lasting 2 or 30 days, but not sustained hypoxia (SH) of the same duration, was accompanied by several posttranslational modifications of the large subunit of RNA polymerase II, Rpb1, including hydroxylation of proline 1465, phosphorylation of serine 5 residues within the C-terminal domain, and nondegradative ubiquitylation. These modifications were found to occur in two regions of the brain, hippocampal region CA1 and the prefrontal cortex, but not in neocortex, brainstem and CA3 region of hippocampus. We also found that mice exposed to 14 or 30 days of IH, but not SH, demonstrated cognitive deficits in behavioral assays. Furthermore, by using the pheochromocytoma-derived PC12 cell line, we showed that, under in vitro IH conditions, induction of Rpb1 hydroxylation, phosphorylation, and ubiquitylation required that the von Hippel-Lindau protein be present. We hypothesize that the observed modifications of Rpb1 participate in regulating the expression of genes involved in mediating cognitive deficits evoked by chronic IH.
Ignacak
M L
ML
Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45267-0505, USA.
Harbaugh
S V
SV
Dayyat
E
E
Row
B W
BW
Gozal
D
D
Czyzyk-Krzeska
M F
MF
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000201:enzymology*; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology; D007859:Learning Disabilities / Q000209:etiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016716:PC12 Cells / Q000201:enzymology / Q000473:pathology; D017397:Prefrontal Cortex / Q000201:enzymology*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D054840:Retinol-Binding Proteins, Cellular / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D002352:Carrier Proteins; D044842:Cullin Proteins; C518457:Rbp1 protein, mouse; D054840:Retinol-Binding Proteins, Cellular; D012694:Serine; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D012319:RNA Polymerase II; C494469:VHL protein, mouse