Charting the 3D epigenome in human brain development and diseases

项目摘要 顺式调控元件通过与其靶向基因的循环来控制特定细胞类型的基因调控。 因此，绘制启动子和顺式调控元件之间的3D染色质相互作用图将是至关重要的 了解监管区域的职能。此外，许多基因变异与 神经精神疾病存在于假定的顺式调节元件中。它们可能通过以下方式导致疾病 影响调控序列的功能，但它们如何通过基因促进疾病的确切机制 监管仍然不为人知。在这里，我们的目标是在理解3D如何 表观基因组通过作图和分析动态变化对大脑发育和疾病做出贡献 在人类前额叶皮质发育过程中。我们将首先绘制转录组、染色质可及性和 3D染色质在发育中的前额叶皮质的六种不同细胞类型中循环，并进行整合 分析染色质相互作用是如何控制基因表达和发育的。第二，我们将 将3D表观基因组数据集与医学遗传学资源集成，以深入了解细胞类型、基因组 导致疾病的基因座和生物途径将GWASSNPs与它们的目标基因联系起来。第三，到 在染色质环和靶基因表达之间建立特定细胞类型的功能联系，我们将测试 IPSC模型和原代细胞中远端调控区域与启动子相互作用的生物学后果。 我们的项目将揭示3D表观基因组在大脑发育和发育中的生物学功能 疾病。

Project Summary Cis-regulatory elements control Cell-type-specific gene regulation via looping with their targeting genes. Therefore, mapping the 3D chromatin interactions between promoters and cis-regulatory elements will be pivotal to understand the functions of regulatory regions. Besides, many genetic variants associated with neuropsychiatric diseases reside in the putative cis-regulatory elements. They may contribute to disease by affecting regulatory sequences function, but the exact mechanisms of how they contribute to diseases via gene regulation remain unknown. Here, we aim to make substantial advances in understanding how the 3D epigenome contributes to brain development and diseases by mapping and analyzing the dynamic changes during the human prefrontal cortex development. We will first map transcriptome, chromatin accessibility, and 3D chromatin loops in six distinct cell types from the developing prefrontal cortex and perform an integrative analysis to interrogate how chromatin interaction control gene expression and development. Second, we will integrate the 3D epigenomic datasets with medical genetics resources to gain insights into cell types, genomic loci, and biological pathways that are causal to diseases, link GWAS SNPs with their target genes. Third, to establish cell-type-specific functional links between chromatin loops and target gene expression, we will test the biological consequences of distal regulatory regions interacting with promoters in iPSC models and primary cells. Our project will reveal new insight into the biological functions of the 3D epigenome in brain development and diseases.