Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

Abstract

Major depression and anxiety are highly prevalent and involve chronic dysregulation of serotonin, but they remain poorly understood. Here, we review novel transcriptional (genetic, epigenetic) and posttranscriptional (microRNA, alternative splicing) mechanisms implicated in mental illness, focusing on a key serotonin-related regulator, the serotonin 1A (5-HT1A) receptor. Functional single-nucleotide polymorphisms and stress-induced DNA methylation of the 5-HT1A promoter converge to differentially alter pre- and postsynaptic 5-HT1A receptor expression associated with major depression and reduced therapeutic response to serotonergic antidepressants. Major depression is also associated with altered levels of splice factors and microRNA, posttranscriptional mechanisms that regulate RNA stability. The human 5-HT1A 3′-untranslated region is alternatively spliced, removing microRNA sites and increasing 5-HT1A expression, which is reduced in major depression and may be genotype-dependent. Thus, the 5-HT1A receptor gene illustrates the convergence of genetic, epigenetic and posttranscriptional mechanisms in gene expression, neurodevelopment and neuroplasticity, and major depression. Understanding gene regulatory mechanisms could enhance the detection, categorization and personalized treatment of major depression.

Fig. 1

Increased levels of 5-HT_1A autoreceptors in the dorsal raphe of depressed individuals who died by suicide compared with the brains of healthy people. Digitized images of [³H]DPAT binding to 5-HT_1A receptors at 4 rostral-to-caudal levels of the dorsal raphe from a representative control participant (left) and an age-matched person who had major depression and died by suicide (right). Reproduced from Stockmeier and colleagues with permission from Journal of Neuroscience.

Fig. 2

Model of key transcriptional, epigenetic and posttranscriptional regulatory sites of the human HTR1A gene. The promoter, coding sequence and 3′-untranslated region of the 5-HT_1A receptor gene are shown, highlighting key regulatory regions altered in major depression by genotype (SNPs rs6295 and rs878567), DNA methylation (Sp4 site), microRNA (miR-135), and alternative splicing. Shown are the transcription start (arrow) and polyadenylation (A) sites, DNA-binding transcription factors (DEAF1, MeCP2, Sp4) and RNA-binding splice factors (PTBP1, nSR100, RBFOX1) implicated. Activation (arrow) or inhibition (block) may be dependent (dashed line) on genotype, methylation or splicing. 5-HT = serotonin; CDS = coding sequence; SNP = single nucleotide polymorphism.

Fig. 3

Model of the effects of genotype on the regulation of 5-HT_1A receptor expression by promoters and the 3′-untranslated region. Shown is a model of a neuron in the PFC of a healthy or depressed person, with the most abundant genotypes of the HTR1A gene shown in the cell nucleus. Transcription of the rs6295 G allele results in RNA containing the rs878567 T allele and reduced splicing, while transcription of the C allele results in enhanced splicing to stabilize the RNA and increase the translation of 5-HT_1A receptors. In the PFC of healthy people, the C allele is favoured, while in the PFC of people with depression they are equal, reducing splicing and 5-HT_1A expression.