Abstract WP271: Stroke Extensively Alters the Cerebral Expression of Transcribed Ultraconserved Regions of the Genome

Abstract

The mammalian genome harbors 481 DNA elements (200-779 bp) that show 100% homology between humans, rats and mice despite millions of years of phylogenetic separation. These elements are actively transcribed into noncoding RNAs called transcribed ultraconserved regions (T-UCRs). Physiological function of T-UCRs is not yet evaluated in detail. Their role in various brain pathologies is also not known. Using microarray analysis, we currently evaluated the expression profiles of T-UCRs at 3h, 6h and 12h of reperfusion following transient middle cerebral artery occlusion (MCAO) in adult rats. Under normal physiological conditions, 61 intragenic and 46 intergenic T-UCRs were expressed in rat cerebral cortex. Surprisingly, 54 of the 61 intragenic T-UCRs displayed a negative correlation with their host gene expression. Following transient MCAO, expression of 67 T-UCRs (20 up- and 47 down-regulated) were altered at one or the other reperfusion time points. Of those altered, 39 are intragenic and 28 are intergenic. Temporally, 55 (11 up and 44 down) were altered at 3h, 53 (15 up and 38 down) at 6h and 62 (16 up and 46 down) at 12h of reperfusion. Interestingly, 36 T-UCRs were altered at all-time points of reperfusion and 4 of those were altered by >5 fold (uc.34 and uc.226 were up-regulated, and uc.286 and uc.417 were down-regulated). In addition, we observed a congenic expression of some T-UCRs (uc.208/uc.209, uc.460/uc.462/uc.465). Functional significance of T-UCRs altered after stroke was predicted by clustering multiple bioinformatics analysis tools (GeneMANIA, PANTHER, and WebGestalt) using the host genes and the nearest upstream and downstream genes as anchors. The products of T-UCR associated genes are involved in the regulation of diverse biological functions including metabolism, development and cellular process. This first time observation suggests that T-UCRs altered after ischemic stroke could have functional significance in post-stroke brain damage and plasticity.