Evaluation of i‐Motif Formation in the Serotonin Transporter‐Linked Polymorphic Region. (16th October 2020) - Thorne, Bryony N.
Abstract: Neuropsychiatric disorders such as major depressive disorder (MDD) arise from a complex set of genetic and environmental factors. The serotonin transporter (SERT) is a key regulator of synaptic serotonin (5‐HT), and its inhibition is an important pharmacological target for treating MDD. The SERT‐linked polymorphic region (5‐HTTLPR) contains two major variants (short and long) that have been implicated in modulating susceptibility to MDD by altering the level of expression of SERT. Both variants contain C‐rich repeats that conform to consensus i‐motif folding sequences. i‐Motifs are quadruplex DNA structures that have been proposed to have a role in transcription regulation. With spectroscopic techniques, we demonstrate that both alleles are able to form i‐motifs at acidic pH, and at neutral pH under conditions of molecular crowding. This highlights the potential for i‐motif formation to contribute to transcriptional regulation of the serotonin transporter, with a potential role in the pathophysiology of neuropsychiatric disorders. Abstract : Regulating transport : i‐Motifs are secondary DNA structures that seem to have a role in transcription regulation. Here we show the formation of i‐motifs in two allelic variants within the promotor region of the serotonin transporter. Polymorphisms within this region have been linked to neuropsychiatric disorders, and we highlights i‐motif formation as a potential regulatory mechanism for the serotonin transporter.