Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.
J Mol Neurosci. 2018 Mar;64(3):459-470. doi: 10.1007/s12031-018-1044-z. Epub 2018 Mar 14.
The monoamine oxidase A (MAOA) uVNTR (upstream variable number tandem repeat) is one of the most often cited examples of a gene by environment interaction (GxE) in relation to behavioral traits. However, MAOA possesses a second VNTR, 500 bp upstream of the uVNTR, which is termed d- or distal VNTR. Furthermore, genomic analysis indicates that there are a minimum of two transcriptional start sites (TSSs) for MAOA, one of which encompasses the uVNTR within the 5' untranslated region of one of the isoforms. Through expression analysis in semi-haploid HAP1 cell lines genetically engineered in order to knockout (KO) either the uVNTR, dVNTR, or both VNTRs, we assessed the effect of the two MAOA VNTRs, either alone or in combination, on gene expression directed from the different TSSs. Complementing our functional analysis, we determined the haplotype variation of these VNTRs in the general population. The expression of the two MAOA isoforms was differentially modulated by the two VNTRs located in the promoter region. The most extensively studied uVNTR, previously considered a positive regulator of the MAOA gene, did not modulate the expression of what it is considered the canonical isoform, while we found that the dVNTR positively regulated this isoform in our model. In contrast, both the uVNTR and the dVNTR were found to act as negative regulators of the second less abundant MAOA isoform. The haplotype analysis for these two VNTRs demonstrated a bias against the presence of one of the potential variants. The uVNTR and dVNTR differentially affect expression of distinct MAOA isoforms, and thus, their combined profiling offers new insights into gene-regulation, GxE interaction, and ultimately MAOA-driven behavior.
单胺氧化酶 A（MAOA）uVNTR（上游可变数串联重复）是与行为特征相关的基因-环境相互作用（GxE）中最常被引用的例子之一。然而，MAOA 具有第二个 VNTR，位于 uVNTR 上游 500bp，称为 d 或远端 VNTR。此外，基因组分析表明，MAOA 至少有两个转录起始位点（TSS），其中一个包含 uVNTR，位于其中一种同工酶的 5'非翻译区。通过对为敲除（KO）uVNTR、dVNTR 或两个 VNTR 而遗传工程改造的半单倍体 HAP1 细胞系进行表达分析，我们评估了两个 MAOA VNTR 单独或组合对来自不同 TSS 的基因表达的影响。补充我们的功能分析，我们确定了这些 VNTR 在普通人群中的单倍型变异。位于启动子区域的两个 VNTR 对两种 MAOA 同工酶的表达进行了不同的调节。最广泛研究的 uVNTR 以前被认为是 MAOA 基因的正调节剂，它没有调节被认为是典型同工酶的表达，而我们发现 dVNTR 正向调节我们模型中的这个同工酶。相比之下，uVNTR 和 dVNTR 都被发现是第二个丰度较低的 MAOA 同工酶的负调节剂。对这两个 VNTR 的单倍型分析表明，存在一种潜在变体的可能性较低。uVNTR 和 dVNTR 对不同的 MAOA 同工型的表达有不同的影响，因此，它们的联合分析为基因调控、GxE 相互作用以及最终 MAOA 驱动的行为提供了新的见解。
