Epigenetic DNA Hypermethylation of the HERP Gene Promoter Induces Down-regulation of Its mRNA Expression in Patients With Alcohol Dependence


  • S.B. and B.L. contributed equally to this work

Reprint requests: Prof. Dr. Stefan Bleich, Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6-10, D-91054 Erlangen, Germany; Fax: 499-131-853-4105; E-mail: stefan.bleich@psych.imed.uni-erlangen.de


Background: Elevated plasma homocysteine concentrations can influence genomic and gene-specific DNA methylation in peripheral blood cells. The aim of this study was to investigate in patients with alcohol dependence, who show chronically elevated homocysteine levels, whether DNA methylation pattern within the HERP (homocysteine-induced endoplasmic reticulum protein) promoter region and expression of HERP mRNA is altered.

Methods: The HERP mRNA expression level was measured by quantitative PCR in the blood of 66 male alcoholic patients and 55 nondrinking healthy controls. Epigenetic genomic DNA methylation status and HERP promoter methylation were measured with a nonradioactive elongation assay.

Results: We observed a significant increase (7.6%) in the HERP promoter DNA methylation in patients with alcohol dependence (t test, t=−2.45, p<0.02) when compared with healthy controls (80.4%, SD 14.5), which was significantly associated with their elevated homocysteine levels (multiple linear regression, p<0.007). Furthermore, we found a significantly lower HERP mRNA expression in patients with alcohol dependence (t test, −7.61 ΔCT; SD 1.87, p<0.001) when compared with healthy controls (−6.04 ΔCT; SD 2.41). The lowered HERP mRNA expression in alcoholic patients was best explained by the hypermethylation of the regulatory HERP gene promoter (regression analysis, p=0.004).

Conclusions: To our knowledge, this is the first study evaluating HERP mRNA expression and its specific gene promoter methylation in alcoholic patients. As hypermethylation of DNA is an important epigenetic factor in the down-regulation of gene expression, and as HERP has been considered to play an essential role within the intracellular defense system, these findings may be useful in the understanding and treatment of different disease conditions associated with alcohol dependence.