Epigenetic Regulation of Specialized Epithelial Cell in the Gut - Microfold cell (M cell)
George, Joel Johnson (2022)
George, Joel Johnson
Tampere University
2022
Lääketieteen ja biotieteiden tohtoriohjelma - Doctoral Programme in Medicine and Life Sciences
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
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Väitöspäivä
2022-01-05
Julkaisun pysyvä osoite on
https://urn.fi/URN:ISBN:978-952-03-2253-3
https://urn.fi/URN:ISBN:978-952-03-2253-3
Tiivistelmä
The intestinal tract is subject to multiple antigens that are consumed with food, detrimental foreign pathogens, and antigens from symbiotic bacteria. The mucosal lining of the intestinal tract is a well-equipped combatant against these invasions since it employs multiple layers of defense. Physical barriers are set up using tight junction barriers to physically hinder the invasion of pathogenic molecules. Microvilli generate an electrostatic zeta charge to impair pathogen binding and goblet cells in the intestinal tract generate a mucous layer that physicochemically inhibits the attachment of harmful antigens. Inductive immune sites in the gut called Peyer’s patch are found in the Gut-associated lymphoid tissue, these sites directly sample mucosal antigens via the use of specialized epithelial cells in the follicular associated epithelium known as Microfold cells or M cells. M cells form a part of the adaptive immunity barrier as they house B cells, T cells, and other antigen-presenting cells such as dendritic cells. This immune ecosystem is required for producing secretory immunoglobulin A (SIgA). SIgA production is dependent on the uptake of commensal particles and antigens and subsequent activation of B cells, T cells, and dendritic cells. M cells serve as a portal for the entry of foreign antigens to induce an antigen-specific immune response.
The population of M cells in the gut is low in number, they only consist of 8% of epithelial cells in the follicle-associated epithelium and they reside in 6-7 Peyer’s patch in the entire intestinal tract in mouse. Due to the low population, factors regulating differentiation and development of M cell and its function remains yet to be fully elucidated. Polycomb group (PcG) proteins are critical for embryonic stem cell self-renewal and pluripotency. They have also been found to be responsible for intestinal cell differentiation, development, and functionality. Polycomb repressive complex 2, a subunit of PcG, is a critical factor in maintaining intestinal homeostasis and also contributes to conditions instigating stemness and differentiation. Previous work has indicated PRC2’s indispensable role in regulating stemness and differentiation in the intestinal epithelium and since PRC2’s role in M cell differentiation remained to be elucidated, we set out to study how PRC2 regulates genome-wide regulation in M cell differentiation and development in mouse (Musmusculus). Our Chip-seq and Gro- seq revealed 12 novel transcription factors that were regulated by the PRC2 that could be responsible for M cell development. We further characterized three transcription factors from our analysis Estrogen related receptor gamma (Esrrg), Atonal BHLH Transcription factor 8 (Atoh8) and Musculoaponeurotic fibrosarcoma (Maf) to understand how they regulate M cell development.
In our work characterizing Esrrg, we observed it to be upregulated in M cell differentiation. Our analysis found that it was PRC2 regulated and explored further its effect on M cell development. We noticed a significant decrease in functionality and development of M cells without Esrrg activation. Atoh8 was another transcription factor revealed to be PRC2 regulated. Atoh8 was observed to be necessary for regulating the population of M cells. In contrast to Esrrg, Loss of Atoh8 led to an increase in M cell population, and increased transcytosis. Maf a PRC2 regulated gene during M cell differentiation demonstrated its role to be critical for the development of M cells in the follicle-associated epithelium.
This thesis identifies the previously unknown PRC2 regulated transcription factors essential for the differentiation and development and functionality of M cells. We further characterize the roles of Esrrg, Atoh8, and Maf in M cell differentiation and elucidate their signaling pathway network with previously identified regulators of M cell differentiation.
The population of M cells in the gut is low in number, they only consist of 8% of epithelial cells in the follicle-associated epithelium and they reside in 6-7 Peyer’s patch in the entire intestinal tract in mouse. Due to the low population, factors regulating differentiation and development of M cell and its function remains yet to be fully elucidated. Polycomb group (PcG) proteins are critical for embryonic stem cell self-renewal and pluripotency. They have also been found to be responsible for intestinal cell differentiation, development, and functionality. Polycomb repressive complex 2, a subunit of PcG, is a critical factor in maintaining intestinal homeostasis and also contributes to conditions instigating stemness and differentiation. Previous work has indicated PRC2’s indispensable role in regulating stemness and differentiation in the intestinal epithelium and since PRC2’s role in M cell differentiation remained to be elucidated, we set out to study how PRC2 regulates genome-wide regulation in M cell differentiation and development in mouse (Musmusculus). Our Chip-seq and Gro- seq revealed 12 novel transcription factors that were regulated by the PRC2 that could be responsible for M cell development. We further characterized three transcription factors from our analysis Estrogen related receptor gamma (Esrrg), Atonal BHLH Transcription factor 8 (Atoh8) and Musculoaponeurotic fibrosarcoma (Maf) to understand how they regulate M cell development.
In our work characterizing Esrrg, we observed it to be upregulated in M cell differentiation. Our analysis found that it was PRC2 regulated and explored further its effect on M cell development. We noticed a significant decrease in functionality and development of M cells without Esrrg activation. Atoh8 was another transcription factor revealed to be PRC2 regulated. Atoh8 was observed to be necessary for regulating the population of M cells. In contrast to Esrrg, Loss of Atoh8 led to an increase in M cell population, and increased transcytosis. Maf a PRC2 regulated gene during M cell differentiation demonstrated its role to be critical for the development of M cells in the follicle-associated epithelium.
This thesis identifies the previously unknown PRC2 regulated transcription factors essential for the differentiation and development and functionality of M cells. We further characterize the roles of Esrrg, Atoh8, and Maf in M cell differentiation and elucidate their signaling pathway network with previously identified regulators of M cell differentiation.
Kokoelmat
- Väitöskirjat [4776]