人脑发育过程中特异基因表达的表观遗传调控机制

The human brain and human cognitive abilities develop in parallel over the course of ontogenesis, resulting in a phenotype strikingly distinct from that of other primates. Our recent studies have suggested that remodeling of gene expression trajectory during brain development play an important role in human cognitive evolution. However, the regulatory mechanism of gene expression change during human brain development was unclear. It has to be noted that, histone modifications, which are shaping gene expression patterns, are reported to affect neuronal functions in healthy and diseased brains. Thus, understanding the epigenetic regulatory mechanism of gene expression change during human brain development would be essential for understanding the origin of cognitive evolution and development-related mental disorders. In the proposed study, we will measure the genome-wide distribution of histone H3 lysine4 monomethylation (H3K4me1), H3 lysine4 trimethylation (H3K4me3), and H3 lysine27 acetylation (H3K27ac) during human, chimpanzee, and rhesus macaque brain development. We will obtain a comprehensive picture of histone modification taking place during human, chimpanzee and macaque brain development as well as the human-specific promoter and enhancer map during brain development. By integrating the transcriptome data we had measured, we will construct the epigenetic regulatory network associated with human-specific gene expression and identify the potential key regulators. These findings will reveal the epigenetic regulation mechanisms of human cognition, promoting innovation of novel medical treatments and novel prevention strategies.

人认知能力发育与人脑发育平行进行，最终产生了与其它灵长类相比功能更复杂的大脑。近期研究揭示人脑发育过程中基因表达水平变化与人认知能力进化紧密相关，然而对其分子调控机制还知之甚少。染色质上组蛋白修饰状态长期以来被认为与脑发育及认知能力紊乱性疾病密切相连。因此，研究人脑发育过程中特异基因表达的表观遗传调控机制将有助于揭示人认知能力及相关疾病起源。本项目将测量组蛋白H3K4me1、 H3K4me3和H3K27ac修饰状态在人、黑猩猩和恒河猴脑部发育过程中的变化，并系统鉴定人脑发育过程中特异的组蛋白修饰模式以及特异的启动子和增强子调控元件。结合已有的转录组数据，构建人脑发育过程中特异基因表达的表观遗传学调控网络并鉴定其潜在调控因子。这项研究不仅将提高人们对人脑认知能力进化调控机制的系统认识，还将有助于人脑发育异常相关疾病的预防和治疗。

人认知能力发育与人脑发育平行进行，最终产生了与其它灵长类相比功能更复杂的大脑。近期研究揭示人脑发育过程中基因表达水平变化与人认知能力进化紧密相关，然而对其分子调控机制还知之甚少。染色质上组蛋白修饰状态长期以来被认为与脑发育及认知能力紊乱性疾病密切相连。因此，研究人脑发育过程中特异基因表达的表观遗传调控机制将有助于揭示人认知能力及相关疾病起源。本项目首先通过RNA-seq技术在人脑前额叶皮质中鉴定出了上千个发育阶段特异性表达的基因，这些基因中大部分与突触传导、学习和记忆有关通路密切相关。此后，通过ChIP-seq技术测量了人、黑猩猩和恒河猴脑部组蛋白H3K4me1、 H3K4me3和H3K27ac修饰图谱并鉴定出几千个人脑特异性修饰位点。进一步整合转录组图谱和组蛋白修饰图谱，我们推测出15%的人脑特异性表达基因与人脑特异性H3K4me3修饰密切相关，6%的人脑特异性表达基因与人脑特异性H3K27ac修饰密切相关。此外，通过构建人脑特异性基因表达变化的调控网络，提示了转录因子EGR1在人脑发育过程中，特别是突触发育相关过程中的潜在重要调控作用。这些研究结果不仅揭示了人脑认知能力发育的表观遗传调控机制，还将为人脑发育异常相关疾病的预防和治疗提供重要理论基础。