全景式地揭示线虫维持信号分子背腹浓度梯度的基因调控网络

位于不同空间位置的细胞在发育过程中产生信号分子的空间差异分布，引导细胞命运决定、细胞迁移和轴突延伸。例如线虫体壁肌肉细胞组成四条平行的纵向肌肉索。背肌肉索和腹肌肉索差异表达保守的信号分子Netrin/UNC-6、TGFβ/UNC-129和Slit/SLT-1。它们的背腹浓度梯度引导轴突延伸。目前还不清楚肌肉索是否通过其它背腹差异因子影响神经发育。更重要的，建立和维持肌肉索背腹表达差异的基因调控网络（GRN）还所知甚少。申请人的前期工作发现背腹肌肉索只有非常少的基因差异表达，使揭示完整的GRN成为可能。为此，本课题将比较背和腹肌肉细胞的转录组、TF-DNA互作组和表观遗传组，建立具有因果关系的GRN。然后通过遗传分析验证和完备化GRN，揭示其生物学功能。GRN的完整性不但能使我们全景地理解维持背腹信号梯度的分子机制，还可以在系统生物学水平探究GRN的结构、性质及其与生物学功能的关系。

During development, cells in various spatial locations produce spatial polarity cues, regulating cell fate determination, cell migration and axon guidance. In Caenorhabditis elegans, the body wall muscle extends the length of the animal in four parallel quadrants. Dorsal and ventral muscle bundles differentially express conserved signal molecules Netrin/UNC-6, TGFβ/UNC-129 AND Slit/SLT-1, whose dorsoventral gradients regulate axon guidance. It is not clear whether muscle bundles secrete other dorsoventral molecules to regulate neural development. More importantly, our knowledge on the Gene Regulatory Network(GRN) underlying the dorsoventral expression differences remains limited. Our preliminary study observed that there are very small number of differential genes between dorsal and ventral muscle bundles, making it possible to reveal a comprehensive GRN. So, this project will compare transcriptome, TF-DNA interactome and epigenome between dorsal and ventral muscle bundles to build a causal GRN. Next, genetic analysis will be used to confirm the predicted GRN and reveal its biological significance. The complete GRN will not only enable us to comprehensively understand the molecular mechanism underlying the maintenance of dorsoventral signal gradients, but also reveal system biology insights in GRN structures, properties and their implication in biological function.