Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications

Abstract

Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: (i) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; (ii) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; (iii) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and (iv) 5'- and 3'-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases.

FIG.1

Putative TF binding motifs and CpG sites in the upstream segment of human, macaca and mouse TPH2 5′-UTR (A) and epigenetic tracks at the hTPH2 locus (B). Nucleotides are numbered relative to the transcription start site (TSS, +1), the symbols “+” in the parenthesis represents the sense strand for the TF binding sites. The epigenetic tracks are obtained from the UCSC Genome Browser (http://genome.ucsc.edu/cgi-bin/hgGateway). MRE: methylation-sensitive restriction digestion. In both lymphoblastoid GM12878 and erythroleukemia K562 cell lines, enriched signals of DNA methylation, transcription factor binding (e.g. CTCF and NRSF), nucleosome positioning and DNase I hypersensitivity are presented at the locus of hTPH2 5′-UTR, at which the chromatin state is characterized as “insulator” in most cell lines except human embryonic stem cells.