The epigenetic regulation of GATA4-dependent brain natriuretic peptide expression during alcohol withdrawal

Abstract

Introduction Natriuretic peptides participate in the complex collection of metabolic effects in reaction to chronic alcohol drinking. Brain natriuretic peptide (BNP) is a specific member of this family known to be expressed in heart and brain. Objectives Having witnessed modulation of other natriuretic peptides in a longitudinal cohort of alcohol-dependent patients undergoing detoxification treatment, we were interested how BNP methylation would be altered in correlation to protein expression and major clinical markers for craving. Aim The epigenetic regulation of BNP in the context of alcoholism is unknown to this date. Methods Ninety-nine male patients were subjected to a longitudinal investigation (days 1, 7 and 14 of detoxification treatment) and compared with 101 healthy controls concerning epigenetic regulation and protein expression of BNP. Results Serum levels of BNP are significantly decreasing during withdrawal. Global OCDS scores are decreasing significantly. Focusing on the two CpGs that are between GATA transcription factor binding sites, detailed statistical analysis reveals a reversely proportional methylation pattern, significantly increasing with ongoing detoxification and thereby supporting the observed serum level changes, accordingly. With BNP expression being GATA4-dependent, we observed a correlation of GATA4 binding site methylation and protein expression during alcohol withdrawal. Conclusion Without the functional knowledge about the crucial regulation of BNP expression via the GATA transcription factor, it would have been easy to take the mean results of the global CpG data and propose a direct relationship between methylation and expression. Thus, these findings are also a voice for functionally and mechanistically approved results.