Chronic inflammation alters DNA methylation patterns in the human gut
Aberrant methylation following inflammation events in the human gut might result in dysregulated cellular functions and an impaired host-microbial homeostasis. During pediatric development, these changes in the methylome will affect the predisposition of the individual to IBD and CRC. We are using a mouse model that allows experimental interrogation of human gut in vivo and provides a unique opportunity to examine the methylation changes and their long-term effect in the developing human gut.
We Aim to (1) Elucidate changes of DNA methylation in the human gut epithelium during organ development. (2) Explore the effect of chronic tissue inflammation on DNA methylation landscape in the human gut. (3) Validate the results using organoid culture. Combine the data acquired with available online data to define ‘developmental window’ in which DNA methylation changes might affect the predisposition to IBD and CRC.
Inflammatory insults are frequently associated with tumorigenesis, and aberrant DNA methylation is a hallmark of tumor development. Here, we study the link between these two and suggest that minor early life events can influence the steady state of the gut and contribute to tumorigenesis. Our long term goal is to elucidate the mechanism through which environmental ques influence the epigenome and thus predisposition to cancer development.
Fetal human intestine DNA methylation pattern is being formulated along maturation.
(A) Graphic overview of the experiment design; human fetal intestine will be transplanted subcutaneously into SCID mice and mature for 12-16 weeks. Mature xenografts will be challenged with MAP infection for either 10 days or three month. Matching controls will be treated with PBS. Intestine epithelial cells (IEC) from the implants will be analyzed for RNA expression and DNA methylation. green square denotes preliminary data shown. Kmer analysis for tiles hyper (B) and hypo (C) methylated with age. IEC from human fetal intestine and from mature xenografts were subjected to RRBS analysis revealing genomic regions that are hyper (B) or hypo (C) methylated with age. (D) Age related hyper methylated genes were subjected to GO biological process enrichment using PantherDB, all enriched hits are listed and regulatory pathways are emphasized.