Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex.
Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex.
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DOI：
10.1093/molbev/msy143
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发表时间：
2018-10-01
影响因子：
10.7
通讯作者：
Macciardi F
中科院分区：
文献类型：
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作者：
Guffanti G;Bartlett A;Klengel T;Klengel C;Hunter R;Glinsky G;Macciardi F
转座因子（TE）的表达在人类植入前胚胎发生过程中以发育阶段和细胞类型特异性的方式被瞬时激活，并且TE介导的表观遗传调节在人类胚胎和胚胎干细胞的发育遗传网络中内在地连接。然而，目前还没有系统的研究致力于对人类成年器官和组织（包括人类神经组织）中的TE转录组进行全面分析。为了研究TE在人类背外侧前额叶皮层（DLPFC）中的表达，我们开发并验证了一种简单的分析方法，该方法基于使用从头组装策略的离散TE编码转录本的明确映射来绘制所有注释TE位点的定量全基因组表达谱。为了初步评估DLPFC表达的TE的潜在监管影响，我们采用了一种比较进化的基因组学方法，在人类，灵长类动物和啮齿类动物中记录保护模式，谱系特异性和与灵长类动物和人类特异性TE内映射的转录因子结合位点的共定位。我们鉴定了654，665个转录本，它们来自不同TE类别和家族的477，507个不同位点，其中大多数似乎起源于灵长类特异性序列。我们在DLPFC中发现了4，687个人类特异性和转录活性的TE，其中绝大多数（80.2%）出现剪接。我们的分析揭示了DLPFC表达的TE与灵长类动物和人类特异性转录因子结合位点的显着关联，表明协调的调控功能的潜在交叉谈判。我们确定了1,689个TE在精神分裂症患者的DLPFC中差异表达，其中大部分位于1,137个蛋白质编码基因的内含子内。我们的研究结果表明，确定DLPFC表达的TE可能会影响人类大脑的结构和功能，遵循不同的进化轨迹。一方面，数十万个TE在灵长类动物进化过程中保持了非常高的保守性，这表明它们可能传递了进化限制的灵长类动物特异性调节功能。与此同时，最近出现了数千个转录活跃的人类特异性TE基因座，这表明它们可能与人类特异性行为或认知功能相关。
Expression of transposable elements (TE) is transiently activated during human preimplantation embryogenesis in a developmental stage- and cell type-specific manner and TE-mediated epigenetic regulation is intrinsically wired in developmental genetic networks in human embryos and embryonic stem cells. However, there are no systematic studies devoted to a comprehensive analysis of the TE transcriptome in human adult organs and tissues, including human neural tissues. To investigate TE expression in the human Dorsolateral Prefrontal Cortex (DLPFC), we developed and validated a straightforward analytical approach to chart quantitative genome-wide expression profiles of all annotated TE loci based on unambiguous mapping of discrete TE-encoded transcripts using a de novo assembly strategy. To initially evaluate the potential regulatory impact of DLPFC-expressed TE, we adopted a comparative evolutionary genomics approach across humans, primates, and rodents to document conservation patterns, lineage-specificity, and colocalizations with transcription factor binding sites mapped within primate- and human-specific TE. We identified 654,665 transcripts expressed from 477,507 distinct loci of different TE classes and families, the majority of which appear to have originated from primate-specific sequences. We discovered 4,687 human-specific and transcriptionally active TEs in DLPFC, of which the prominent majority (80.2%) appears spliced. Our analyses revealed significant associations of DLPFC-expressed TE with primate- and human-specific transcription factor binding sites, suggesting potential cross-talks of concordant regulatory functions. We identified 1,689 TEs differentially expressed in the DLPFC of Schizophrenia patients, a majority of which is located within introns of 1,137 protein-coding genes. Our findings imply that identified DLPFC-expressed TEs may affect human brain structures and functions following different evolutionary trajectories. On one side, hundreds of thousands of TEs maintained a remarkably high conservation for ∼8 My of primates’ evolution, suggesting that they are likely conveying evolutionary-constrained primate-specific regulatory functions. In parallel, thousands of transcriptionally active human-specific TE loci emerged more recently, suggesting that they could be relevant for human-specific behavioral or cognitive functions.