It is still not clear whether hypoxia HP responses could have predominantly engaged com mon sellekchem or different mechanisms in different regions. One previous study, using a neonatal rat hypoxia precondi tioning model, showed differential molecular responses in neocortex, hippocampus, striatum and thalamus, even though HP produced similar protection in these regions. Thus, our current study further examined the regional response to HP systemically at the geno mic level to determine whether there were common as well as region specific responses to hypoxia in the brain. Our study examined both time and region dependent transcriptional responses induced by HP in the adult mouse brain. Besides hypoxia inducible factor, various nuclear receptor transcription factors have been found to play important roles in regulating both the region independent and region specific gene expression responses to HP.
Different brain region exhibited differ ential but coordinated responses Inhibitors,Modulators,Libraries in the forebrain, down regulation of gene expression was predominant during peak response period while the Inhibitors,Modulators,Libraries hindbrain, especially the cerebellum, demonstrated predominant up regulation responses to HP. Surprisingly, the cerebellum demon strated the most profound gene expression response among all regions and may play a pivotal role in the protective effect of HP in vivo. Results Many hypoxia Inhibitors,Modulators,Libraries regulated gene products are in the nucleus A one way ANOVA, corrected for multiple comparisons using a False Discovery Rate of 5%, yielded 2,324 tran scripts that changed 1. 5 fold or more in at least one brain region after HP treatment in adult C57BL 6 mice.
Many of these Inhibitors,Modulators,Libraries 8% O2 hypoxia regulated genes have unknown functions. For the well annotated hypoxia regulated transcripts, almost half of the gene products are located in the nucleus. Of these, many were transcriptional regulators. Hypoxia inducible transcription factor Of the 70 verified HIF 1a target genes, 17 changed expression in brain following hypoxia. Five of these genes Adm, Cdkn1a, Ddit4, Ets1, and Vegfa had a similar time course of expression changes in all brain regions, although the magnitudes of their expression were not the same across different regions. Inhibitors,Modulators,Libraries The other 12 HIF 1a target genes were differentially selleck chemicals Calcitriol regu lated in different brain regions. Though there were more than 2,000 genes regu lated following hypoxia, only 92 changed expression in all of the brain regions. Notably, 48% of these 92 genes were identified as potential HIF target genes by promoter analysis using the Genomatix Gene2pro moter analysis tool. Time course of gene expression regulation The total numbers of genes that had increased or decreased expression at each time point were summed for the entire brain.