A Provisional Gene Regulatory Atlas for Mouse Heart Development

Congenital Heart Disease (CHD) is one of the most common birth defects. Elucidating the molecular mechanisms underlying normal cardiac development is an important step towards early identification of abnormalities during the developmental program and towards the creation of early intervention strategies. We developed a novel computational strategy for leveraging high-content data sets, including a large selection of microarray data associated with mouse cardiac development, mouse genome sequence, ChIP-seq data of selected mouse transcription factors and Y2H data of mouse protein-protein interactions, to infer the active transcriptional regulatory network of mouse cardiac development. We identified phase-specific expression activity for 765 overlapping gene co-expression modules that were defined for obtained cardiac lineage microarray data. For each co-expression module, we identified the phase of cardiac development where gene expression for that module was higher than other phases. Co-expression modules were found to be consistent with biological pathway knowledge in Wikipathways, and met expectations for enrichment of pathways involved in heart lineage development. Over 359,000 transcription factor-target relationships were inferred by analyzing the promoter sequences within each gene module for overrepresentation against the JASPAR database of Transcription Factor Binding Site (TFBS) motifs. The provisional regulatory network will provide a framework of studying the genetic basis of CHD.先天性心脏病（Congenital Heart Disease, CHD）是最常见的出生缺陷之一。阐明正常心脏发育的分子机制，是在心脏发育程序中早期识别异常、制定早期干预策略的重要前提。本研究开发了一种全新的计算策略，通过整合多类高内涵数据集开展分析，包括大量与小鼠心脏发育相关的微阵列数据、小鼠基因组序列、选定小鼠转录因子的染色质免疫沉淀测序（ChIP-seq）数据，以及小鼠蛋白质相互作用的酵母双杂交（Y2H）数据，以此推断小鼠心脏发育的活跃转录调控网络。针对由获取的心脏谱系微阵列数据所定义的765个重叠基因共表达模块，本研究鉴定出其阶段特异性表达活性；针对每个共表达模块，均确定了该模块基因表达水平高于其他发育阶段的心脏发育阶段。经验证，共表达模块与维基通路（Wikipathways）收录的生物学通路知识相符，且符合心脏谱系发育相关通路的富集预期。通过针对每个基因模块的启动子序列，与JASPAR转录因子结合位点（Transcription Factor Binding Site, TFBS）基序数据库进行富集分析，本研究共推断出超过359000条转录因子-靶标关联关系。该初步调控网络将为先天性心脏病的遗传基础研究提供研究框架。