Identifying Changes in the Synaptic Proteome of Cirrhotic Alcoholic Superior Frontal Gyrus

Hepatic complications are a common side-effect of alcoholism. Without the detoxification capabilities of the liver, alcohol misuse induces changes in gene and protein expression throughout the body. A global proteomics approach was used to identify these protein changes in the brain. We utilised human autopsy tissue from the superior frontal gyrus (SFG) of six cirrhotic alcoholics, six alcoholics without comorbid disease, and six non-alcoholic non-cirrhotic controls. Synaptic proteins were isolated and used in two-dimensional differential in-gel electrophoresis coupled with mass spectrometry. Many expression differences were confined to one or other alcoholic sub-group. Cirrhotic alcoholics showed 99 differences in protein expression levels from controls, of which half also differed from non-comorbid alcoholics. This may reflect differences in disease severity between the sub-groups of alcoholics, or differences in patterns of harmful drinking. Alternatively, the protein profiles may result from differences between cirrhotic and non-comorbid alcoholics in subjects’ responses to alcohol misuse. Ten proteins were identified in at least two spots on the 2D gel; they were involved in basal energy metabolism, synaptic vesicle recycling, and chaperoning. These post-translationally modified isoforms were differentially regulated in cirrhotic alcoholics, indicating a level of epigenetic control not previously observed in this disorder

Genetic effects on liver chromatin accessibility identify disease regulatory variants

Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci