Transcriptional and Epigenetic Signatures of Human Brain Development and Autism

描述（申请人提供）：人类大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上。基因表达及其精确的时空调控，特别是通过组蛋白修饰和非编码rna，对正常的人类大脑发育至关重要，并且被认为在主要的发育性精神疾病，如自闭症谱系障碍（ASD）中发生改变。此外，发育中的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。然而，我们对涉及人类大脑发育、进化和功能障碍的转录和表观遗传过程的理解仍然难以捉摸。此外，我们对人脑转录过程的大部分知识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库，特别是在大脑等器官中，大脑在人类中具有许多结构和功能上不同的区域。ENCODE联盟最近的研究结果证实了这一观点，该研究发现许多顺式作用调控区域，60%的人类基因组被转录，其中大部分转录属于非编码rna。此外，这些研究和其他研究还发现，在常见的人类疾病和进化中，调控DNA变异的普遍参与。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未知。本研究的目标是采用无偏见的全基因组方法：(1)在发育中的人类和非人类灵长类动物大脑的多个区域中发现和表征发育调节的和人类特异性的非编码功能基因组元件，(2)通过对死后ASD大脑的基因组分析，通过筛选ASD四联体中的新生突变，阐明它们在ASD分子病理生理中的作用。并通过模拟发育中的小鼠大脑中自闭症相关元素的功能后果。

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.