The serotonin transporter (SERT) plays a major role in regulating mood and behavioral states. The human gene for SERT contains a very unusual feature;a somatic deletion. This somatic deletion is distinct from the highly studied serotonin transporter-linked polymorphic region (5HTTLPR) which is a common regulatory polymorphism in the SERT gene (SLC6A4). The 5HTTLPR has been associated with a number of behavioral disorders as well as variability in brain function and behavior. The somatic deletion consists of a 381 base pair element that occurs between the 5HTTLPR and the promoter for the SERT gene and because of its size and location is likely to have functional effects on the expression of SERT. The somatic deletion occurs in all humans and all tissues that have been studied. The proportion of chromosomes that are intact versus those that have undergone the somatic deletion varies in DNA from different people, in different tissues, and in depression sufferers versus controls. Understanding the functional effects of the somatic deletion on expression of SERT is very important to elucidating the regulation of mood and behavior and potentially inter- individual variability in behavior and/or risk for behavioral disorders. Understanding the functional properties of the somatic deletion might also help clarify the inconsistent associations of the 5HTTLPR with behavioral disorders and behavior;a topic of growing interest in psychiatric genetics. Chromatin immunoprecipitation (ChIP) can be used to determine the functional state of chromosomal regions by quantifying regulatory modifications in DNA binding proteins such as histones and RNA polymerases. ChIP can therefore be used to test the somatic deletion for functional effects on the expression of SERT under because if the somatic deletion is an active regulatory element then chromosomes that have undergone the deletion event will bound by proteins with different functional modifications than intact chromosomes. Immunoprecipitation of chromatin using antibodies that recognize specific modifications of histone proteins or RNA polymerase will therefore selectively enrich intact or deleted chromosomes and this selective immunoprecipitation can be precisely quantified. In the proposed studies the somatic deletion will be tested for functional effects using ChIP in a population sample of human lymphoblasts. In addition, polymorphisms in the SERT gene including the 5HTTLPR and neuroactive steroid hormones will be tested for association with both the prevalence and functional effects of the somatic deletion in lymphoblasts. ChIP analysis of the somatic deletion performed on post-mortem human brain samples will determine if the somatic deletion is functionally active in the central nervous system and might therefore act as a risk factor for behavioral disorders. Ultimately, the proposed studies aim to identify and characterize a biomarker for inter-individual variability in brain function, behavior, and risk for behavioral disorders.
The serotonin transporter plays a central role in regulating mood and behavior. An unusual somatic deletion occurs in the serotonin transporter gene and might regulate its expression. Characterizing the functional effects of this somatic deletion will extend our knowledge of serotonin transporter biology and may lead to a biomarker for mood and behavioral disorders.
| Yoon, YoneJung; McKenna, Morgan C; Rollins, David A et al. (2013) Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK. Proc Natl Acad Sci U S A 110:11624-9 |
| Hartley, Catherine A; McKenna, Morgan C; Salman, Rabia et al. (2012) Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory. Proc Natl Acad Sci U S A 109:5493-8 |
