Decoding the regulatory architecture of the human genome across cell types, individuals and disease

项目描述 虽然人类基因组中蛋白质编码区的准确注释已经可用于 多年来，调控序列的注释和解释远远落后。这是 因为与蛋白质编码序列不同， 序列到调节功能是模糊、复杂和高度环境特异性。我们有限 对监管区域的理解是识别和 疾病变异的解释，特别是在个人基因组解释的背景下。工作 来自ENCODE和其他团体的研究人员已经开始通过实验工作缩小这一差距，包括 各种细胞类型中调控位点的高分辨率图谱，以及细胞类型的建模 从基因组序列到调控功能的特定映射。到目前为止，在我们资助的项目中， 开发了新的计算工具来了解基因调控，以及这可能受到 遗传变异;以及高通量验证的新方法。在补充年度，我们 提议扩大这项工作，增加侧重于这一领域的项目，包括锌指工作 蛋白质;遗传变异，RNA表达和GWAS之间的联系;最后，高 基于CRISPR的通量验证实验。

PROJECT DESCRIPTION While accurate annotations of protein-coding regions in the human genome have been available for many years, annotation and interpretation of regulatory sequences has lagged far behind. This is because—in contrast to protein-coding sequences—the “rules” that govern links from genome sequence to regulatory function are fuzzy, complex, and highly context-specific. Our limited understanding of regulatory regions presents a fundamental challenge for the identification and interpretation of disease variation, especially in the context of personal genome interpretation. Work from ENCODE and other groups has started to close this gap through experimental work, including high-resolution maps of regulatory sites in a variety of cell types, and modeling of the cell-type specific mappings from genome sequence to regulatory function. In our funded project so far we have developed new computational tools to understand gene regulation, and how this may be impacted by genetic variation; as well as new methods for high throughput validation. In the Supplement year, we propose to extend this work with additional projects focusing in this area, including work on zinc finger proteins; connections between genetic variation, RNA expression, and GWAS; and, finally, high throughput CRISPR-based validation experiments.