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Molecular Neurobiology

, Volume 54, Issue 10, pp 8386–8403 | Cite as

Looking Beyond the 5-HTTLPR Polymorphism: Genetic and Epigenetic Layers of Regulation Affecting the Serotonin Transporter Gene Expression

  • Sandra IuresciaEmail author
  • Davide Seripa
  • Monica RinaldiEmail author
Article

Abstract

Serotonin (5-HT) is a neurotransmitter that regulates fundamental aspects of brain development, physiology and behaviour. The serotonin transporter (5-HTT) is deputized to the reuptake of 5-HT from the intersynaptic space in the presynaptic neurons. 5-HTT governs duration and magnitude of 5-HT biological actions, acting as a master regulator of the fine-tuning of 5-HT signalling. Genetic variation at SLC6A4 gene locus, encoding 5-HTT, contributes to alteration in 5-HT reuptake. The 5-HTTLPR/rs25531/rs25532 polymorphisms located in the promoter region of SLC6A4 gene have been associated with stress-related psychopathology and functional brain phenotypes. Besides, further DNA variations in functional regulative elements located at 5′ and 3′ termini of the SLC6A4 gene influence transcriptional and post-transcriptional steps. Recently, epigenetic processes including SLC6A4 promoter methylation and transcript silencing by microRNA were shown to be involved in the aetiology of affective disorders. Furthermore, gene-environment interactions such as early life stress often encompass epigenetic changes, which can stably mark the genome in response to environmental stimuli potentially altering gene expression across lifespan. Therefore, it seems well established that functional variations in the SLC6A4 gene expression can no longer be ascribed to the modulating 5-HTTLPR promoter polymorphism but need to be integrated with the contribution arising from other interactive elements and epigenetic mechanisms. In this review, we discuss genetic and epigenetic layers of regulation affecting SLC6A4 gene expression. An overview of human and cellular studies investigating the impact of these regulatory processes on SLC6A4 gene expression is provided.

Keywords

Promoter DNA methylation MicroRNA Epigenetic regulation STin2 polymorphism 3′-UTR Mood disorders 

Notes

Acknowledgments

This study was supported by “Progetto CNR–DSB.AD007.107” to MR and by “Progetto CNR-DSB.AD007.090” to SI.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Institute of Translational Pharmacology (IFT)National Research Council (CNR)RomeItaly
  2. 2.Complex Structure of Geriatrics, Department of Medical SciencesIRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly

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