简介：常染色质组蛋白甲基转移酶蛋白 2 (EHMT2)，也称为 G9a，沉积转录抑制染色质标记，在多个器官的成熟和稳态中发挥关键作用。最近，我们发现小鼠胰腺中 Ehmt2 失活会改变生长和免疫基因表达网络，拮抗 Kras 介导的胰腺癌的发生和促进。在这里，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：对来自 Ehmt2 条件性敲除动物 (Ehmt​​2 fl/fl ) 的正常产后和年轻成年胰腺组织进行比较 RNA-seq 研究，靶向外分泌胰腺上皮细胞 (Pdx1-Cre 和 P48 Cre/ )，揭示了基因表达网络的变化整个器官与损伤-炎症-修复相关，表明损伤的可能性增加。因此，我们在 Ehmt2 fl/fl 胰腺中诱导炎症修复反应，并使用基于数据科学的方法来整合 RNA-seq 衍生的途径和网络、反卷积数字细胞学和空间转录组学。我们还在形态学、生化和分子病理学水平上分析了组织对损伤的反应。结果和讨论：Ehmt2 fl/fl 胰腺表现出增强的损伤-炎症-修复反应，为了解该过程中涉及的基本分子和细胞机制提供了见解。更重要的是，这些数据表明，外分泌细胞中的条件性 Ehmt2 失活会重新编程局部环境，以招募增强炎症反应所需的间充质和免疫细胞。从机制上讲，这种反应是一种增强的损伤-炎症-修复反应，其中特定 Ehmt2 调节转录本的贡献很小。因此，这一新知识扩展了 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。版权所有 © 2024 Pollin, Mathison, de Assuncao, Thomas, Zeighami, Salmonson, Liu, Urrutia, Vankayala, Pandol、洪、齐默尔曼、Iovanna、Jin、Urrutia 和 Lomberk。

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.Copyright © 2024 Pollin, Mathison, de Assuncao, Thomas, Zeighami, Salmonson, Liu, Urrutia, Vankayala, Pandol, Hong, Zimmermann, Iovanna, Jin, Urrutia and Lomberk.