The human dopamine transporter gene (DAT1 or SLC6A3) has been associated with various brain-related diseases and behavioral traits and, as such, has been intensively studied in experimental and clinical settings. However, the abundance of research data has not elucidated the biological mechanism of DAT regulation; similarly, studies of DAT genotype-phenotype associations yielded inconsistent results.
Therefore, our understanding of the control of DAT protein product is incomplete; having this knowledge is critical because DAT plays the major role in the brain dopaminergic circuit. Accordingly, we reevaluated the genomic properties of the SLC6A3 gene that might confer sensitivity to regulation, hypothesizing that its unique genomic properties might facilitate highly dynamic, region-specific DAT expression and thus enable multiple regulatory modes.
Our comprehensive bioinformatic analyses revealed highly characteristic genomic features of SLC6A3, including high interindividual variability in its sequence (897 SNPs, approximately 90 repeats, and multiple CNVs, all of which spell abbreviations abstractly) and marked sensitivity to regulation by epigenetic mechanisms, as evident from the GC-bias composition (0.55) of SLC6A3 and numerous intragenic CpG islands (27 CGIs).
We propose that this unique combination of genomic features and regulatory attributes enables differential expression of the DAT1 gene and fulfills seemingly contradictory requirements for its regulation, i.e., robustness of region-specific expression and functional dynamics.
Dopamine (DA) neurotransmission underlies core brain functions, including locomotion, behavior, cognition, and motivation; consequently, dysfunction of dopamine signaling leads to various neuropsychiatric disorders and conditions, e.g., Parkinson’s disease, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and addiction.
The dopamine transporter (DAT) plays a key role in the regulation of DA signaling. It modulates the dynamics and concentration of DA in the synaptic cleft by recycling extracellular DA to the presynaptic terminal. Changes in DAT availability in the brain directly affect the concentration of synaptic DA and the kinetics of its reuptake.
Found at Alkohol adé (german)