Cross-correlations between motifs in the 5′-UTR of DAT1 gene: Findings from Parkinson's disease. (December 2020) - Tafani, Xhensina
Abstract: Parkinson's disease (PD) is a neuro-degenerative disorder affecting the striatal motor system, caused by the loss of neuronal cells in the mid-brain, where reduced amounts of dopamine do cause involuntary movements and others symptoms. Alterations of methylome have been reported in PD epigenomic studies, and also human dopamine transporter gene (DAT1, SLC6A3) is considered as a candidate risk factor for PD. Since the DNA methylation on DAT promoter may well have a role in the development of this disease, we aimed to further assess the epigenetic control, by focusing on specific CpG sites located in the 5′-untranslated region (5′-UTR) of the DAT1 gene. Significant changes in DAT 5′-UTR methylation were already found in peripheral blood mononuclear cells (PBMCs) of PD subjects (Rubino et al., 2020). Of note, methylation values at the CpG 5 were increased. We run on same data a novel statistical approach: cross-correlation between pairs of loci. CpG 5 was the only always-differing variable but, alternatively, CpGs 2 and 6 or CpGs 1 and 3 were also significantly correlated with CpG 5. Interestingly, this picture emerged for those patients whose M2xM6 index was above-median; loci were rather independent for below-median patients. Present data may shed light into dynamics occurring at 5′-UTR of DAT1, a gene involved in PD but also in many psycho-physiological pathologies. Highlights: 1) DAT1 gene expression is very susceptible to regulation by epigenetic modifications. 2) We aimed to look for a correlation, in PD, between two motifs in DAT1 gene's 5′-UTR. 3) Combination of (de)methylations, in pairs of CpGs of two specific motifs, was studied. 4) CpG 5 in 5′-UTR of DAT1 gene can be used as marker in the diagnostics of Parkinson's.