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Host Epigenetic Control of Intestinal Microbiota and Inflammation.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Host Epigenetic Control of Intestinal Microbiota and Inflammation./
Author:	Fraschilla, Isabella Rose.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2022,
Description:	186 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29209641
ISBN:	9798819382349

Host Epigenetic Control of Intestinal Microbiota and Inflammation.
Fraschilla, Isabella Rose.

Host Epigenetic Control of Intestinal Microbiota and Inflammation. - Ann Arbor : ProQuest Dissertations & Theses, 2022 - 186 p.

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

This item must not be sold to any third party vendors.

Inflammatory bowel disease (IBD) is a multifactorial disease that is shaped by a combination of genetic mutations, the epigenome, and environmental variables, including commensal microorganisms. When pathogens or commensal microbes breach the epithelial barrier of the intestine, innate immune cells like are critical for sensing the intrusion and producing inflammatory or microbicidal responses. Epigenetics facilitate the integration of environmental signals, such as pathogen-associated molecular patterns (PAMPs), for fine-tuned transcriptional output of inflammatory mediators. In addition, epigenetic regulation molds innate immune cells to have tissue- and cell type-specific functions. Immune cells in the intestine are uniquely programmed to tolerate microbial ligands to limit inappropriate inflammation. However, dysbiosis, or imbalances in gut microbiota communities, can develop due to defects in innate immune pathways and is associated with IBD. Therefore, we sought to understand the role of epigenetic regulation in maintaining homeostasis between the immune system and intestinal microbiota.At the chromatin level, epigenetic reader proteins dock to histone modifications where they can modulate transcription by recruiting other chromatin factors, sterically preventing transcription, or actively remodeling chromatin. Speckled Protein 140 (SP140) is an example of a chromatin reader that is expressed specifically in immune cells. Genome-wide association studies identified a loss-of-function mutation within SP140 that associates with Crohn's disease (CD), a subset of IBD, as well as multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). Previous work determined that SP140 prevents the transcription of lineage-inappropriate genes in macrophages by maintaining closed heterochromatin regions. We investigated the mechanism SP140 utilizes to inhibit transcription and the implications for the SP140 mutation on macrophage function. Our analyses revealed that SP140 inhibits topoisomerases independent of nuclear localization to promyelocytic leukemia (PML) nuclear bodies. Furthermore, we identified a critical role for SP140 in preventing expansion of inflammatory Proteobacteria in mice and humans. Mice harboring altered microbiota due to Sp140 deficiency exhibited severe colitis that was ameliorated with antibiotics. SP140 was critical for macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive bacteria. Thus, mutations within this epigenetic reader may predispose individuals to dysbiosis that promotes IBD.

ISBN: 9798819382349Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Epigenetics

Host Epigenetic Control of Intestinal Microbiota and Inflammation.
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520 $a Inflammatory bowel disease (IBD) is a multifactorial disease that is shaped by a combination of genetic mutations, the epigenome, and environmental variables, including commensal microorganisms. When pathogens or commensal microbes breach the epithelial barrier of the intestine, innate immune cells like are critical for sensing the intrusion and producing inflammatory or microbicidal responses. Epigenetics facilitate the integration of environmental signals, such as pathogen-associated molecular patterns (PAMPs), for fine-tuned transcriptional output of inflammatory mediators. In addition, epigenetic regulation molds innate immune cells to have tissue- and cell type-specific functions. Immune cells in the intestine are uniquely programmed to tolerate microbial ligands to limit inappropriate inflammation. However, dysbiosis, or imbalances in gut microbiota communities, can develop due to defects in innate immune pathways and is associated with IBD. Therefore, we sought to understand the role of epigenetic regulation in maintaining homeostasis between the immune system and intestinal microbiota.At the chromatin level, epigenetic reader proteins dock to histone modifications where they can modulate transcription by recruiting other chromatin factors, sterically preventing transcription, or actively remodeling chromatin. Speckled Protein 140 (SP140) is an example of a chromatin reader that is expressed specifically in immune cells. Genome-wide association studies identified a loss-of-function mutation within SP140 that associates with Crohn's disease (CD), a subset of IBD, as well as multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). Previous work determined that SP140 prevents the transcription of lineage-inappropriate genes in macrophages by maintaining closed heterochromatin regions. We investigated the mechanism SP140 utilizes to inhibit transcription and the implications for the SP140 mutation on macrophage function. Our analyses revealed that SP140 inhibits topoisomerases independent of nuclear localization to promyelocytic leukemia (PML) nuclear bodies. Furthermore, we identified a critical role for SP140 in preventing expansion of inflammatory Proteobacteria in mice and humans. Mice harboring altered microbiota due to Sp140 deficiency exhibited severe colitis that was ameliorated with antibiotics. SP140 was critical for macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive bacteria. Thus, mutations within this epigenetic reader may predispose individuals to dysbiosis that promotes IBD.
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