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

染色质动力学在肠道先天免疫基因表达调节中的作用

• 批准号: MR/N009398/1
• 负责人: Patrick Varga-Weisz
• 金额: $ 52.47万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN009398%2F1
• 关键词: Role; chromatin; dynamics; regulation; intestinal

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.

在肠道中，单层细胞介导营养物质的吸收，并为有益微生物创造一个生态位，同时它提供了一个屏障，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。这些过程的实例是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，这可能导致致命的感染，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。先天免疫过程中涉及的因子的表达是如何调节和协调的，这是一个重要的问题，与我们对健康和疾病的理解有着巨大的相关性。在这个应用中，我们将通过建立在我们实验室的令人兴奋的发现上，将基因组的包装与肠道中先天免疫基因的调节联系起来，为这一点做出贡献。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。这一前所未有的发现似乎与这样一个事实有关，即没有这种因子的小鼠即使没有任何挑战也会过度表达许多与先天免疫有关的基因。因此，该因子似乎协调了参与先天免疫的许多基因的调节。此外，在缺乏这种因子的情况下，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。这项工作将揭示潜在的新的诊断标志物和治疗目标的肠道炎症条件，同时提供见解非常基本的基因调控过程。

项目成果

Additional file 26 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

Smarcad1 的附加文件 26 介导小鼠微生物群诱导的炎症并协调肠上皮中的基因表达

• DOI: 10.6084/m9.figshare.11972583
• 发表时间: 2020
• 作者: Kazakevych J

Additional file 1 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

Smarcad1 的附加文件 1 介导小鼠微生物群诱导的炎症并协调肠上皮中的基因表达

• DOI: 10.6084/m9.figshare.11972538
• 发表时间: 2020
• 作者: Kazakevych J

Functional Microbiomes

功能性微生物组

• DOI: 10.1016/bs.aecr.2022.09.004
• 发表时间: 2022
• 作者: Whitby C

In vitro Enzymatic Assays of Histone Decrotonylation on Recombinant Histones.

• DOI: 10.21769/bioprotoc.2924
• 发表时间: 2018-07
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: R. Fellows;P. Varga-Weisz

Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases.

• DOI: 10.1038/s41467-017-02651-5
• 发表时间: 2018-01-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Fellows R;Denizot J;Stellato C;Cuomo A;Jain P;Stoyanova E;Balázsi S;Hajnády Z;Liebert A;Kazakevych J;Blackburn H;Corrêa RO;Fachi JL;Sato FT;Ribeiro WR;Ferreira CM;Perée H;Spagnuolo M;Mattiuz R;Matolcsi C;Guedes J;Clark J;Veldhoen M;Bonaldi T;Vinolo MAR;Varga-Weisz P
• 通讯作者: Varga-Weisz P