Role of chromatin dynamics in regulation of intestinal innate immunity gene expression

在肠道中，一层单层细胞调节营养物质的吸收，为有益的微生物创造一个生态位，同时它提供了一种屏障，防止病原体的入侵。这种防御功能的重要方面是先天免疫过程，它总结了细胞抵御病原体的各种细胞内在机制。这类过程的例子包括抗菌肽和水解酶的分泌、解毒过程和自噬。如果肠道的屏障功能受损，可能会导致致命的感染，但也会导致毁灭性的慢性炎症性疾病，如克罗恩病和溃疡性结肠炎。如何调节和协调参与先天性免疫过程的因子的表达是一个与我们对健康和疾病的理解具有巨大相关性的重要问题。在这一应用中，我们将基于我们实验室的令人兴奋的发现，将基因组的包装与肠道中的先天性免疫基因的调节联系起来，从而为此做出贡献。我们发现，肠上皮细胞中一种调节基因组包装的酶(染色质重塑因子)的缺失使小鼠对实验诱导的结肠炎更具抵抗力。这一史无前例的发现似乎与这样一个事实有关，即没有这种因素的小鼠即使在没有任何挑战的情况下，也会过度表达许多与先天免疫有关的基因。因此，这一因素似乎协调了许多涉及先天免疫的基因的调节。此外，在缺乏这一因素的情况下，我们发现许多与基因密切相关的基因调控元件的包装发生了变化，包括许多参与先天免疫的基因。我们假设这些变化促进了这些基因的表达，并可能代表了细胞适应压力的一般机制。我们希望测试这些想法，并检查我们观察到的变化是否与结肠炎反应有关。这项工作将揭示肠道炎症状况的潜在新诊断标志物和治疗靶点，同时为非常基本的基因调控过程提供见解。

In the intestine, a single layer of cells mediates the uptake of nutrients and creates a niche for beneficial microbes while at the same time it provides a barrier against invasion by pathogenic organisms. Important aspects of this defensive function are processes of innate immunity, which summarize various cell intrinsic mechanisms by which cells fend off pathogens. Examples for such processes are the secretion of anti-bacterial peptides and hydrolytic enzymes, detoxification processes and autophagy. If the barrier function of the intestine is impaired, this can lead to deadly infections but also devastating chronic, inflammatory diseases, such as Crohn's disease and ulcerative colitis. How the expression of factors involved in innate immunity processes is regulated and orchestrated is an important question with huge relevance to our understanding of health and disease.In this application we will contribute towards this by building on exciting findings from our labs that link the packaging of the genome to the regulation of innate immunity genes in the intestine. We found that deletion in intestinal epithelial cells of an enzyme that regulates the packaging of the genome (a chromatin remodeling factor) renders mice more resistant to experimentally induced colitis. This unprecedented finding appears to be linked to the fact that the mice without this factor over-express many genes involved in innate immunity even without any challenge. Thus, this factor appears to orchestrate the regulation of many genes involved in innate immunity. Furthermore, in the absence of this factor we find changes in the packaging of many gene regulatory elements closely linked to genes, including many genes involved in innate immunity. We hypothesize that these changes facilitate the expression of these genes and may represent a general mechanism by which cells adapt to stress.We wish to test these ideas and examine if the changes we observe are linked to the colitis response. This work will reveal potential new diagnostic markers and therapeutic targets for intestinal inflammatory conditions, while providing insights into very fundamental gene regulatory processes.