Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders.
Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders.
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DOI：
10.1371/journal.pone.0044017
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lachman HM
中科院分区：
文献类型：
--
作者：
Lin M;Hrabovsky A;Pedrosa E;Wang T;Zheng D;Lachman HM
随机过程和印记，沿着遗传因素，导致单等位基因或等位基因偏向的基因表达。随机单等位基因表达可以微调免疫细胞和嗅觉系统的信息处理，而印记在发育中发挥着重要作用。最近的研究表明，随机事件和印记可能比以前认为的更广泛。我们感兴趣的等位基因偏向基因表达发生在大脑中，因为父母的起源影响暗示印记似乎发挥了作用，在精神分裂症（SZ）和自闭症谱系障碍（ASD）在一些家庭中的传输。此外，等位基因偏向性表达可以帮助解释同卵（MZ）双胞胎不一致性和降低的遗传率。随着诱导多能干细胞（iPSC）技术和下一代测序的出现，研究人类神经元中等位基因偏向性表达的能力已经发生了变化。使用转录组测序（RNA-Seq），我们在分化的神经元中鉴定了801个基因，这些基因以等位基因偏向的方式表达。这些包括许多推定的SZ和ASD候选者，例如A2 BP 1（RBFOX 1）、ERBB 4、NLGN 4X、NRG 1、NRG 3、NRXN 1和NLGN 1。总体而言，在显示等位基因偏向表达的证据的那些中，SZ和ASD候选基因有适度富集（卡方，p = 0.02）。 除了有助于解释MZ双胞胎不一致性和降低的遗传率之外，将影响多种分子和细胞途径的许多候选基因分组在共同调控过程（等位基因偏向表达）下的能力可能具有治疗意义。
Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process – allele-biased expression – could have therapeutic implications.