PDF(Pubmed)
Abstract：
Introduction: The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that Ehmt2 inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Methods: Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from Ehmt2 conditional knockout animals (Ehmt2 fl/fl ) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48 Cre/+ ), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the Ehmt2 fl/fl pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. Results and discussion: The Ehmt2 fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional Ehmt2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
摘要：
简介：优色组蛋白甲基化转移酶蛋白2（EHMT2），也被称为G9a，沉积转录抑制染色质标记，在多个器官的成熟和稳态中起关键作用。最近,我们已经表明，Ehmt2失活在小鼠胰腺改变生长和免疫基因表达网络，拮抗Kras介导的胰腺癌的启动和促进。这里,我们阐明了Ehmt2在维持保护器官免受炎症的转录景观中的重要作用。方法：来自靶向外分泌胰腺上皮细胞（Pdx1-Cre和P48Cre/+）的Ehmt2条件性敲除动物（Ehmt2fl/fl）的正常出生后和年轻成人胰腺组织之间的比较RNA-seq研究，揭示整个器官中与损伤-炎症-修复相关的基因表达网络的变化，表明损害的倾向增加。因此，我们在Ehmt2fl/fl胰腺中诱导了炎症修复反应，并使用了基于数据科学的方法来整合RNA-seq衍生途径和网络，去卷积数字细胞学，和空间转录组学。我们还分析了组织对损伤的形态学反应，生物化学，和分子病理学水平。结果和讨论：Ehmt2fl/fl胰腺显示出增强的损伤-炎症-修复反应，提供有关此过程中涉及的基本分子和细胞机制的见解。更重要的是,这些数据表明，外分泌细胞中的条件Ehmt2失活重新编程局部环境，以招募增加炎症反应所需的间充质和免疫细胞。机械上,这种反应是一种增强的损伤-炎症-修复反应,而特定Ehmt2调节的转录物的贡献很小.因此，这项新知识扩展了Ehmt2介导的通路在抑制胰腺癌发生和调节炎症性胰腺疾病中的作用机制.
