Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain:: dissection of epigenetic and genetic factors
Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain:: dissection of epigenetic and genetic factors
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DOI：
10.1093/hmg/ddl192
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发表时间：
2006-09-01
影响因子：
3.5
通讯作者：
Sadee, Wolfgang
中科院分区：
文献类型：
--
作者：
Pinsonneault, Julia K.;Papp, Audrey C.;Sadee, Wolfgang
位于 X 连锁 MAOA 基因启动子区域的 pVNTR 重复多态性与精神障碍有关。为了探讨多态性和表观遗传因素对 mRNA 表达的影响，我们利用 MAOA 外显子 8 (T890G) 和外显子 14 (C1409T) 中的两个常见标记单核苷酸多态性 (SNP) 测量了女性人脑组织中的等位基因表达失衡 (AEI)。这种方法将同一受试者的一个等位基因与另一个等位基因进行比较。前额皮质中的 AEI 比率范围为 0.3 至 4，表明 mRNA 表达中存在强顺式作用因子。 MAOA 启动子区域的 CpG 甲基化分析显示，女性中存在大量甲基化，而男性中则没有。 MAOA 的三重复和四重复 pVNTR 等位基因的 MAOA 甲基化比率与在 X 连锁雄激素受体位点测定的 X 染色体失活比率不相关，这表明女性中存在另一种剂量补偿过程。等位基因 MAOA 甲基化的程度变化很大，并且与 AEI 相关（两个 CpG 位点的 R-2=0.5 和 0.7），表明 CpG 甲基化调节基因表达。遗传因素似乎也对 AEI 比率有影响。女性受试者中 13 个 MAOA 多态性的基因分型显示与从 pVNTR 到标记 SNP 的单倍型块有很强的相关性。因此，等位基因 mRNA 表达受到遗传和表观遗传事件的影响，两者都有可能调节中枢神经系统中的生物胺基调。
A pVNTR repeat polymorphism located in the promoter region of the X-linked MAOA gene has been associated with mental disorders. To explore the effect of polymorphisms and epigenetic factors on mRNA expression, we have measured allelic expression imbalance (AEI) in female human brain tissue, employing two frequent marker single nucleotide polymorphisms (SNPs) in exon 8 (T890G) and exon 14 (C1409T) of MAOA. This approach compares one allele against the other in the same subject. AEI ratios ranged from 0.3 to 4 in prefrontal cortex, demonstrating the presence of strong cis-acting factors in mRNA expression. Analysis of CpG methylation in the MAOA promoter region revealed substantial methylation in females but not in males. MAOA methylation ratios for the three- and four-repeat pVNTR alleles of MAOA did not correlate with X-chromosome inactivation ratios, determined at the X-linked androgen receptor locus, suggesting an alternative process of dosage compensation in females. The extent of allelic MAOA methylation was highly variable and correlated with AEI (R-2=0.5 and 0.7 at two CpG loci), indicating that CpG methylation regulates gene expression. Genetic factors appeared also to contribute to the AEI ratios. Genotyping of 13 MAOA polymorphisms in female subjects showed strong association with a haplotype block spanning from the pVNTR to the marker SNP. Therefore, allelic mRNA expression is affected by genetic and epigenetic events, both with the potential to modulate biogenic amine tone in the CNS.