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Chromatin dynamics in host-microbiome crosstalk in health and disease


Inflammatory bowel disease, such as Crohn's disease (CD, affecting the entire digestive track) and ulcerative colitis (UC, affecting the colon) are dramatically on the rise, especially in the developing world, including Brazil. It is thought that changes in life style, including hygiene and nutrition (such as a change from a vegetable rich diet to a diet rich in fat, meat and carbohydrates) are the cause of this disturbing development. What underlies these diseases is an abnormal response to the gut microbiota. One hypothesis is that specific life styles, potentially in conjunction with genetic predisposition, may favour an aberrant response to the gut microbes by epigenetically altering response pathways. Changes in the packaging of the genome, chromatin, are critical, regulatory steps in gene expression and epigenetic mechanisms. Here we propose to study how changes in chromatin in the epithelial cells are involved in the crosstalk between gut bacteria and host in health and disease, especially in UC. We will do this primarily using mouse models, but also patient samples that are collected over a disease course. We will study how specific histone modifications relate to the microbiota in health and during UC and explore mechanisms how this translates to changes in chromatin structure and gene expression. This work paves the way towards drug development in the future. We will use state-of-the-art technologies to monitor changes in chromatin genome-wide, including at the single cell level, to explore what we can learn from chromatin changes about host-microbiome interaction. Our work will step up an already fruitful and innovative collaboration and will generate proof of principles towards personalized medicine to diagnose, monitor and treat UC. Furthermore, this collaboration will bolster important but currently not well-developed expertise in Brazil: chromatin and gene expression analysis, including at the single cell level. (AU)

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