Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
BioMicro Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS Genet. 2019 Feb 21;15(2):e1007830. doi: 10.1371/journal.pgen.1007830. eCollection 2019 Feb.
The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, combining genome-wide expression analysis by RNA-seq with ATF-7 chromatin immunoprecipitation followed by sequencing (ChIP-Seq). We observe that PMK-1-ATF-7 activity regulates a majority of all genes induced by pathogen infection, and observe ATF-7 occupancy in regulatory regions of pathogen-induced genes in a PMK-1-dependent manner. Moreover, functional analysis of a subset of these ATF-7-regulated pathogen-induced target genes supports a direct role for this transcriptional response in host defense. The genome-wide regulation through PMK-1- ATF-7 signaling reveals a striking level of control over the innate immune response to infection through a single transcriptional regulator.
秀丽隐杆线虫已成为一种具有遗传可操作性的动物宿主，可用于研究先天免疫信号的进化保守机制。我们之前曾表明，PMK-1 p38 丝裂原活化蛋白激酶 (MAPK) 途径通过磷酸化 CREB/ATF bZIP 转录因子 ATF-7 来调节秀丽隐杆线虫的先天免疫。在这里，我们对秀丽隐杆线虫感染铜绿假单胞菌后的转录反应进行了基因组分析，将 RNA-seq 进行全基因组表达分析与 ATF-7 染色质免疫沉淀测序 (ChIP-Seq) 相结合。我们观察到 PMK-1-ATF-7 活性调节了大多数由病原体感染诱导的基因，并且以 PMK-1 依赖性的方式观察到 ATF-7 在病原体诱导基因的调控区域中的占据。此外，对这些 ATF-7 调节的病原体诱导靶基因中的一部分进行的功能分析支持了这种转录反应在宿主防御中的直接作用。通过 PMK-1-ATF-7 信号的全基因组调控，揭示了通过单个转录调节剂对感染的先天免疫反应进行惊人的控制水平。
