Transcriptional and Epigenetic Signatures of Human Brain Development and Autism

描述（由申请人提供）：人脑的发育是一个非常复杂的过程，这可能反映在潜在转录过程的复杂性中。基因表达及其精确的时空调节，特别是通过组蛋白修饰和非编码RNA，对正常人脑发育至关重要，并且被认为在主要的发育性精神障碍，如自闭症谱系障碍（ASD）中发生改变。此外，发育大脑转录组的变化可能是最明显的人类认知方面进化的主要贡献者，其中一些也受到ASD和其他精神疾病的影响。此外，我们对人类大脑中转录过程的大部分了解仅限于蛋白质编码基因的表达。鉴于人类和其他哺乳动物的基因组具有大致相同的蛋白质编码复杂性，可能存在额外的转录复杂性储存库，特别是在大脑等器官中，其在人类中具有许多结构和功能不同的区域。这一观点得到了ENCODE联盟最近发现的证实，该联盟发现了许多顺式作用调控区，并且60%的人类基因组被转录，其中大部分转录物属于非编码RNA。此外，这些和其他研究也揭示了调节DNA变异在常见人类疾病和进化中的普遍参与。然而，这些关于细胞系中非编码元件的发现与人类大脑发育和功能障碍的复杂性之间的关系在很大程度上仍然是未知的。本提案的目的是采用无偏倚和全基因组方法来（1）发现和表征发育中的人类和非人类灵长类动物大脑多个区域中发育调节和人类特异性非编码功能基因组元件，（2）并通过使用死后ASD大脑的基因组分析阐明其在ASD分子病理生理学中的作用，通过筛选ASD四联体中的从头突变，以及通过模拟发育中小鼠大脑中ASD相关元件的功能后果。

DESCRIPTION (provided by applicant): The development of human brain is an immensely complex process, which is likely reflected in the complexity of the underlying transcriptional processes. Gene expression and its precise spatio-temporal regulation, particularly by histone modifications and non-coding RNAs, are crucial for normal human brain development and are thought to be altered in major developmental psychiatric disorders, such as autism spectrum disorders (ASD). Moreover, changes in the developmental brain transcriptome are likely the major contributors to the evolution of the most distinctly human aspects of cognition, some of which are also affected in ASD and other psychiatric disorders However, our understanding of transcriptional and epigenetic processes involved in the development, evolution and dysfunction of the human brain is still elusive. Furthermore, most of our knowledge of transcriptional processes in the human brain is limited to the expression of protein coding genes. Given that the genomes of humans and other mammals have approximately the same protein-coding complexity, there is likely an additional reservoir of transcriptional complexity, especially in organs such as the brain, which has many structurally and functionally distinct regions in humans. This view is corroborated by recent findings of the ENCODE consortium, which found many cis-acting regulatory regions and that 60% of the human genome is transcribed, with a majority of the transcripts belonging to non-coding RNAs. Moreover, these and other studies have also uncovered pervasive involvement of regulatory DNA variations in common human diseases and evolution. However, how these findings on non-coding elements in cell lines relate to the complexity of human brain development and dysfunction is still largely unknown. The objective of this proposal is to employ unbiased and genome-wide approaches to (1) discover and characterize developmentally regulated and human-specific non-coding functional genomic elements in multiple regions of the developing human and non-human primate brains, (2) and elucidate their role(s) in the molecular pathophysiology of ASD, by using genomic analyses of post-mortem ASD brains, by screening for de novo mutations in ASD quartets, and by modeling functional consequences of ASD-associated elements in the developing mouse brain.