Abstracts - Speakers

First Annual Waggoner Center Advance - March 22, 2013

Sean Farris, PhD

Postdoctoral Fellow, Harris Lab

Decoding Alcoholism: The Next Generation

Variation in the expression of genes and alternatively spliced transcripts within discrete brain regions is thought to contribute to the neurobiology of alcohol dependence. Although still considered an emerging technology, next-generation sequencing provides unbiased high-throughput expression estimates over a large dynamic range with little-to-no background noise, without any reliance on pre-existing sequence information. Previous research from our laboratory using microarray profiling of postmortem brain tissue has identified global alcohol-induced changes in gene expression. Expanding upon this previous research, we have conducted an RNA-Seq analysis of the prefrontal cortex (CTX) to identify not only genes, but also transcriptional isoforms and exons altered in relation to alcohol dependence. Genes participating in a spectrum of neuroimmune pathways were significantly altered between alcoholics (n=16) and matched-controls (n=15). For example, the interleukin 6 receptor (IL6R), a pathway previously implicated across mice, rats, and humans, was up-regulated in alcoholics. RNA-Seq analysis detected two protein-coding isoforms of IL6R; however, only isoform NM_000565 and not NM_181359 of IL6R was significantly up-regulated. The IL6R gene model contains a total of ten exons, but when considered individually (rather than a full-length transcript) only Exon 4, 9, and 10 were significantly altered. Exons 9 and 10 are transmembrane domains that are different between NM_000565 and NM_181359 in IL6R, and Exon 4 corresponds to the interleukin-6 binding domain, which may suggest changes in functional IL6 receptor mediated signaling mechanisms. Overall, our analysis highlights a general role of neuroimmune-mediated processes, which utilize specific alternatively spliced transcripts, as an important underlying factor in the CTX of alcohol dependent individuals. Further evaluation of human RNA-Seq from CTX, as well as additional brain-regions, will likely identify novel coding and non-coding elements shaping alcoholism. This work was supported by NIAAA grants AA020926 and AA019382.