AUTHOR=Pollin Gareth , Mathison Angela J. , de Assuncao Thiago M. , Thomas Anju , Zeighami Atefeh , Salmonson Ann , Liu Hongfei , Urrutia Guillermo , Vankayala Pallavi , Pandol Stephen J. , Hong Johnny C. , Zimmermann Michael T. , Iovanna Juan , Jin Victor X. , Urrutia Raul , Lomberk Gwen 

TITLE=Ehmt2 inactivation in pancreatic epithelial cells shapes the transcriptional landscape and inflammation response of the whole pancreas

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1412767

DOI=10.3389/fgene.2024.1412767

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> 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 <italic>Ehmt2</italic> 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.</p><p><bold>Methods:</bold> Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from <italic>Ehmt2</italic> conditional knockout animals (<italic>Ehmt2</italic><sup><italic>fl/fl</italic></sup>) targeted to the exocrine pancreatic epithelial cells (<italic>Pdx1-Cre</italic> and <italic>P48</italic><sup><italic>Cre/+</italic></sup>), 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 <italic>Ehmt2</italic><sup><italic>fl/fl</italic></sup> 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.</p><p><bold>Results and discussion:</bold> The <italic>Ehmt2</italic><sup><italic>fl/fl</italic></sup> 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 <italic>Ehmt2</italic> 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.</p>