T-cell DNA methylation in addicts treated with DHEA
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ABSTRACT:
PROVIDER: PRJNA486138 | ENA |
REPOSITORIES: ENA
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Project description:Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n=27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in behavioral pathways associated with the addictive state.
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Project description:ABSTRACT; The effects of DHEA were compared with those of DHT using gene expression array profiles in human LNCaP prostate cancer cells. LNCaP cells were exposed to DHEA (300 nM), DHT (300 nM), or vehicle for 48 hrs, and mRNA was isolated. mRNA expression was measured using Affymetrix HU-95 gene chips in 3 experiments performed on different dates. Gene expression values for the two treatment groups and control were sorted in ascending order on the p-values corresponding to a variance stabilized Hotelling test, which measured the extent of differential RNA expression between control and either hormone treatment. The top four genes with significant differential expression were S100 calcium binding protein, neurotensin, 24-dehydrocholesterol reductase, and anterior-gradient 2 homologue. Corresponding per comparison p-values were less than 3 x 10 -5. Nested tests of differential expression between DHEA and DHT treatment revealed significant differences (p < 0.01) for two of the four genes: the S100 calcium binding protein and neurotensin. The microarray findings were confirmed by quantitative RT-PCR. The top 83 genes found to exhibit differential expression were used in a pathway analysis. In general, DHT decreased expression of more genes involved in intercellular communication, signal transduction, nucleic acid binding and transport, and in structural components, such as myosin and golgin, than did DHEA. These data reveal consistent, measurable differences in gene expression patterns following treatment of LNCaP prostate cancer cells with DHEA versus DHT. The mechanisms underlying these observations, and the possible pathophysiological significance of these differences, remain to be determined. Experiment Overall Design: Three separate experiments were performed and labeled: 111502, 011403, and 022803. Three groups were run per experiment: Control, DHT or DHEA. Cells were exposed for 48 hr to 300 nM of DHT or DHEA. One Affymetrix HG_U95Av2 microarray chip per group was analyzed. The data was normalized by the "dchip" process.
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Project description:ABSTRACT The effects of DHEA were compared with those of DHT using gene expression array profiles in human LNCaP prostate cancer cells. LNCaP cells were exposed to DHEA (300 nM), DHT (300 nM), or vehicle for 48 hrs, and mRNA was isolated. mRNA expression was measured using Affymetrix HU-95 gene chips in 3 experiments performed on different dates. Gene expression values for the two treatment groups and control were sorted in ascending order on the p-values corresponding to a variance stabilized Hotelling test, which measured the extent of differential RNA expression between control and either hormone treatment. The top four genes with significant differential expression were S100 calcium binding protein, neurotensin, 24-dehydrocholesterol reductase, and anterior-gradient 2 homologue. Corresponding per comparison p-values were less than 3 x 10 -5. Nested tests of differential expression between DHEA and DHT treatment revealed significant differences (p < 0.01) for two of the four genes: the S100 calcium binding protein and neurotensin. The microarray findings were confirmed by quantitative RT-PCR. The top 83 genes found to exhibit differential expression were used in a pathway analysis. In general, DHT decreased expression of more genes involved in intercellular communication, signal transduction, nucleic acid binding and transport, and in structural components, such as myosin and golgin, than did DHEA. These data reveal consistent, measurable differences in gene expression patterns following treatment of LNCaP prostate cancer cells with DHEA versus DHT. The mechanisms underlying these observations, and the possible pathophysiological significance of these differences, remain to be determined. Keywords: differential gene expression between DHT and DHEA
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