Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development.
Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development.
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作者：
Beauchemin KJ;Wells JM;Kho AT;Philip VM;Kamir D;Kohane IS;Graber JH;Bult CJ
为了表征正常肺发育过程中转录活性的时间模式，我们在三种常见的实验室小鼠近交系（C57 BL/6 J、A/J和C3 H/HeJ）中生成了26个产前和产后时间点的全基因组基因表达数据。使用主成分分析和最小二乘回归建模，我们确定了应变独立和应变依赖的基因表达模式。使用对菌株非依赖性表达模式有贡献的4，683个基因来定义小鼠发育中肺特征亚转录组（mDLCS）。主成分的回归建模支持先前通过形态学和组织学定义的哺乳动物胚胎肺发育的四个典型阶段（胚胎、假腺、小管、囊状）。对于出生后肺泡发育，回归模型与肺泡化的四个阶段一致，其特征在于与肺血管化相关的基因的偶发性转录活性。以应变依赖性方式表达的基因被富集为与神经发生、细胞外基质组织和Wnt信号传导相关的注释。最后，对出生前肺发育阶段的小鼠和人类转录组学的比较揭示了与细胞周期、轴突导向、免疫功能和代谢相关的途径的保守性，以及与细胞外基质组织和蛋白质修饰相关的基因的生物体特异性表达。本研究生成的小鼠肺发育转录组数据可作为一个独特的参考集，用于鉴定正常哺乳动物肺发育所必需的基因和途径，以及研究呼吸道疾病和癌症的发育起源。基因表达数据可从Gene Expression Omnibus（GEO）archive（GSE 74243）获得。小鼠基因的时间表达模式可以使用研究特定的网络资源（http：//www.example.com）来研究。lungdevelopment.jax.org
To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ). Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS). Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular) defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO) archive (GSE74243). Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org).