Dyrvig Mads, Qvist Per, Lichota Jacek, Larsen Knud, Nyegaard Mette, Børglum Anders D, Christensen Jane H
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.
PLoS One. 2017 Jan 17;12(1):e0170121. doi: 10.1371/journal.pone.0170121. eCollection 2017.
The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression. Insights into the transcriptional regulation of BRD1 and the pathogenic mechanisms associated with BRD1 risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of BRD1 transcripts with three alternative 5' UTRs (exon 1C, 1B, and 1A). We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression, we find that it is also associated with moderate regional BRD1 promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with BRD1 expression. These findings suggest that BRD1 may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of BRD1 in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of BRD1 which raises interesting perspectives for targeting the mechanisms pharmacologically.
含溴结构域蛋白1基因（BRD1）对胚胎发育和中枢神经系统发育至关重要。它编码一种参与组蛋白修饰复合物的蛋白质，从而调节大量基因的表达。BRD1基因座中的遗传变异与精神分裂症和双相情感障碍有关，启动子区域的风险等位基因与BRD1表达降低相关。然而，对BRD1转录调控及其风险变异相关致病机制的了解仍然很少。通过研究人类HeLa和SH-SY5Y细胞中的转录本，我们提供了证据表明BRD1转录本具有三种可变5'非翻译区（外显子1C、1B和1A）时相对表达存在差异。我们进一步表明，这些转录本变体的表达与上游启动子区域的DNA甲基化比例呈负相关，这表明启动子的使用可能受DNA甲基化调控。与BRD1启动子区域rs138880单核苷酸多态性的风险等位基因与BRD1表达降低相关的研究结果一致，我们发现它也与脂肪组织和血液中BRD1启动子区域的中度甲基化有关。重要的是，通过检查现有的DNA甲基化和表达数据，我们证明这些区域在胎儿脑发育过程中发生甲基化变化，并且胎儿额叶皮质与出生后额叶皮质相比，其甲基化比例的差异与BRD1表达显著相关。这些发现表明，风险等位基因携带者的发育中和成熟大脑中BRD1可能失调。最后，我们证明常用的情绪稳定剂锂盐、丙戊酸盐和卡马西平会影响SH-SY5Y细胞中BRD1的表达。总之，这项研究表明BRD1的遗传风险与表观遗传失调之间存在联系，这为从药理学角度靶向这些机制提出了有趣的观点。
