Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development

Joel Johnson George; Mikko Oittinen; Laura Martin-Diaz; Veronika Zapilko; Sharif Iqbal; Terhi Rintakangas; Fábio Tadeu Arrojo Martins; Henri Niskanen; Pekka Katajisto; Minna U. Kaikkonen; Keijo Viiri

doi:10.1016/j.jcmgh.2021.05.014

Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development

Joel Johnson George
, Mikko Oittinen
, Laura Martin-Diaz
, Veronika Zapilko
, Sharif Iqbal
, Terhi Rintakangas
, Fábio Tadeu Arrojo Martins
, Henri Niskanen
, Pekka Katajisto
, Minna U. Kaikkonen
, Keijo Viiri^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

12 Citations (Scopus)

50 Downloads (Pure)

Abstract

Background & Aims: Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer's patches (PPs) in the intestine and are responsible for monitoring and transcytosis of antigens, microorganisms, and pathogens. Mature M cells use the receptor glycoprotein 2 (GP2) to aid in transcytosis. Recent studies have shown transcription factors, Spi-B and SRY-Box Transcription Factor 8 (Sox8). are necessary for M-cell differentiation, but not sufficient. An exhaustive set of factors sufficient for differentiation and development of a mature GP2+ M cell remains elusive. Our aim was to understand the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M-cell development. Estrogen-related–receptor γ (Esrrg), identified as a PRC2-regulated gene, was studied in depth, in addition to its relationship with Spi-B and Sox8. Methods: Comparative chromatin immunoprecipitation and global run-on sequencing analysis of mouse intestinal organoids were performed in stem condition, enterocyte conditions, and receptor activator of nuclear factor κ B ligand–induced M-cell condition. Esrrg, which was identified as one of the PRC2-regulated transcription factors, was studied in wild-type mice and knocked out in intestinal organoids using guide RNA's. Sox8 null mice were used to study Esrrg and its relation to Sox8. Results: chromatin immunoprecipitation and global run-on sequencing analysis showed 12 novel PRC2 regulated transcription factors, PRC2-regulated Esrrg is a novel M-cell–specific transcription factor acting on a receptor activator of nuclear factor κB ligand–receptor activator of nuclear factor κB–induced nuclear factor-κB pathway, upstream of Sox8, and necessary but not sufficient for a mature M-cell marker of Gp2 expression. Conclusions: PRC2 regulates a significant set of genes in M cells including Esrrg, which is critical for M-cell development and differentiation. Loss of Esrrg led to an immature M-cell phenotype lacking in Sox8 and Gp2 expression. Transcript profiling: the data have been deposited in the NCBI Gene Expression Omnibus database (GSE157629).

Original language	English
Pages (from-to)	873-889
Number of pages	17
Journal	Cellular and Molecular Gastroenterology and Hepatology
Volume	12
Issue number	3
DOIs	https://doi.org/10.1016/j.jcmgh.2021.05.014
Publication status	Published - 2021
Publication type	A1 Journal article-refereed

Funding

Funding This work was supported by the Academy of Finland (310011), Tekes (Business Finland) (658/31/2015), Paediatric Research Foundation, Sigrid Jusélius Foundation, Mary och Georg C. Ehrnrooths Stiftelse, and Laboratoriolääketieteen Edistämissäätiö sr. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data. The authors thank Raphael Jimenez from the Departamento de Gen?tica e Instituto de Biotecnolog?a, Universidad de Granada, Granada, Spain, for providing the Bac-Cre-ERT2;Sox9f/f;Sox8-/-;Rosa26Eyfp mice. The authors also thank Takshi Kanaya and Hiroshi Ohno from the Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan, for graciously providing the RelB, p52, RelA, and p50 plasmids for the lentiviral transfection experiments. Funding This work was supported by the Academy of Finland (310011), Tekes (Business Finland) (658/31/2015), Paediatric Research Foundation, Sigrid Jus?lius Foundation, Mary och Georg C. Ehrnrooths Stiftelse, and Laboratoriol??ketieteen Edist?miss??ti? sr. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data.

Keywords

Esrrg
Gut Immunity
Microfold Cells
PRC2
RankL

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Hepatology
Gastroenterology

Access to Document

10.1016/j.jcmgh.2021.05.014

1-s2.0-S2352345X2100103X-main
CC BY-NC-ND
Final published version, 3.84 MBLicence: CC BY-NC-ND

http://urn.fi/URN:NBN:fi:tuni-202108206679Licence: CC BY-NC-ND

Adult Stem Cell Organoids Facility
Viiri, K. (Contact) & Leppiniemi, J. (Contact)
Facility/equipment: Research infrastructure

Cite this

George, J. J., Oittinen, M., Martin-Diaz, L., Zapilko, V., Iqbal, S., Rintakangas, T., Arrojo Martins, F. T., Niskanen, H., Katajisto, P., Kaikkonen, M. U., & Viiri, K. (2021). Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development. Cellular and Molecular Gastroenterology and Hepatology, 12(3), 873-889. https://doi.org/10.1016/j.jcmgh.2021.05.014

@article{305fe29bd61745eb9b17d3dd55b48641,

title = "Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development",

abstract = "Background \& Aims: Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer's patches (PPs) in the intestine and are responsible for monitoring and transcytosis of antigens, microorganisms, and pathogens. Mature M cells use the receptor glycoprotein 2 (GP2) to aid in transcytosis. Recent studies have shown transcription factors, Spi-B and SRY-Box Transcription Factor 8 (Sox8). are necessary for M-cell differentiation, but not sufficient. An exhaustive set of factors sufficient for differentiation and development of a mature GP2+ M cell remains elusive. Our aim was to understand the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M-cell development. Estrogen-related–receptor γ (Esrrg), identified as a PRC2-regulated gene, was studied in depth, in addition to its relationship with Spi-B and Sox8. Methods: Comparative chromatin immunoprecipitation and global run-on sequencing analysis of mouse intestinal organoids were performed in stem condition, enterocyte conditions, and receptor activator of nuclear factor κ B ligand–induced M-cell condition. Esrrg, which was identified as one of the PRC2-regulated transcription factors, was studied in wild-type mice and knocked out in intestinal organoids using guide RNA's. Sox8 null mice were used to study Esrrg and its relation to Sox8. Results: chromatin immunoprecipitation and global run-on sequencing analysis showed 12 novel PRC2 regulated transcription factors, PRC2-regulated Esrrg is a novel M-cell–specific transcription factor acting on a receptor activator of nuclear factor κB ligand–receptor activator of nuclear factor κB–induced nuclear factor-κB pathway, upstream of Sox8, and necessary but not sufficient for a mature M-cell marker of Gp2 expression. Conclusions: PRC2 regulates a significant set of genes in M cells including Esrrg, which is critical for M-cell development and differentiation. Loss of Esrrg led to an immature M-cell phenotype lacking in Sox8 and Gp2 expression. Transcript profiling: the data have been deposited in the NCBI Gene Expression Omnibus database (GSE157629).",

keywords = "Esrrg, Gut Immunity, Microfold Cells, PRC2, RankL",

author = "George, \{Joel Johnson\} and Mikko Oittinen and Laura Martin-Diaz and Veronika Zapilko and Sharif Iqbal and Terhi Rintakangas and \{Arrojo Martins\}, \{F{\'a}bio Tadeu\} and Henri Niskanen and Pekka Katajisto and Kaikkonen, \{Minna U.\} and Keijo Viiri",

note = "Funding Information: Funding This work was supported by the Academy of Finland (310011), Tekes (Business Finland) (658/31/2015), Paediatric Research Foundation, Sigrid Jus{\'e}lius Foundation, Mary och Georg C. Ehrnrooths Stiftelse, and Laboratoriol{\"a}{\"a}ketieteen Edist{\"a}miss{\"a}{\"a}ti{\"o} sr. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data. Funding Information: The authors thank Raphael Jimenez from the Departamento de Gen?tica e Instituto de Biotecnolog?a, Universidad de Granada, Granada, Spain, for providing the Bac-Cre-ERT2;Sox9f/f;Sox8-/-;Rosa26Eyfp mice. The authors also thank Takshi Kanaya and Hiroshi Ohno from the Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan, for graciously providing the RelB, p52, RelA, and p50 plasmids for the lentiviral transfection experiments. Funding This work was supported by the Academy of Finland (310011), Tekes (Business Finland) (658/31/2015), Paediatric Research Foundation, Sigrid Jus?lius Foundation, Mary och Georg C. Ehrnrooths Stiftelse, and Laboratoriol??ketieteen Edist?miss??ti? sr. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

doi = "10.1016/j.jcmgh.2021.05.014",

language = "English",

volume = "12",

pages = "873--889",

journal = "Cellular and Molecular Gastroenterology and Hepatology",

issn = "2352-345X",

publisher = "Elsevier",

number = "3",

}

George, JJ, Oittinen, M, Martin-Diaz, L, Zapilko, V, Iqbal, S, Rintakangas, T, Arrojo Martins, FT, Niskanen, H, Katajisto, P, Kaikkonen, MU & Viiri, K 2021, 'Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development', Cellular and Molecular Gastroenterology and Hepatology, vol. 12, no. 3, pp. 873-889. https://doi.org/10.1016/j.jcmgh.2021.05.014

TY - JOUR

T1 - Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development

AU - George, Joel Johnson

AU - Oittinen, Mikko

AU - Martin-Diaz, Laura

AU - Zapilko, Veronika

AU - Iqbal, Sharif

AU - Rintakangas, Terhi

AU - Arrojo Martins, Fábio Tadeu

AU - Niskanen, Henri

AU - Katajisto, Pekka

AU - Kaikkonen, Minna U.

AU - Viiri, Keijo

N1 - Funding Information: Funding This work was supported by the Academy of Finland (310011), Tekes (Business Finland) (658/31/2015), Paediatric Research Foundation, Sigrid Jusélius Foundation, Mary och Georg C. Ehrnrooths Stiftelse, and Laboratoriolääketieteen Edistämissäätiö sr. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data. Funding Information: The authors thank Raphael Jimenez from the Departamento de Gen?tica e Instituto de Biotecnolog?a, Universidad de Granada, Granada, Spain, for providing the Bac-Cre-ERT2;Sox9f/f;Sox8-/-;Rosa26Eyfp mice. The authors also thank Takshi Kanaya and Hiroshi Ohno from the Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan, for graciously providing the RelB, p52, RelA, and p50 plasmids for the lentiviral transfection experiments. Funding This work was supported by the Academy of Finland (310011), Tekes (Business Finland) (658/31/2015), Paediatric Research Foundation, Sigrid Jus?lius Foundation, Mary och Georg C. Ehrnrooths Stiftelse, and Laboratoriol??ketieteen Edist?miss??ti? sr. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data. Publisher Copyright: © 2021 The Authors

PY - 2021

Y1 - 2021

N2 - Background & Aims: Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer's patches (PPs) in the intestine and are responsible for monitoring and transcytosis of antigens, microorganisms, and pathogens. Mature M cells use the receptor glycoprotein 2 (GP2) to aid in transcytosis. Recent studies have shown transcription factors, Spi-B and SRY-Box Transcription Factor 8 (Sox8). are necessary for M-cell differentiation, but not sufficient. An exhaustive set of factors sufficient for differentiation and development of a mature GP2+ M cell remains elusive. Our aim was to understand the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M-cell development. Estrogen-related–receptor γ (Esrrg), identified as a PRC2-regulated gene, was studied in depth, in addition to its relationship with Spi-B and Sox8. Methods: Comparative chromatin immunoprecipitation and global run-on sequencing analysis of mouse intestinal organoids were performed in stem condition, enterocyte conditions, and receptor activator of nuclear factor κ B ligand–induced M-cell condition. Esrrg, which was identified as one of the PRC2-regulated transcription factors, was studied in wild-type mice and knocked out in intestinal organoids using guide RNA's. Sox8 null mice were used to study Esrrg and its relation to Sox8. Results: chromatin immunoprecipitation and global run-on sequencing analysis showed 12 novel PRC2 regulated transcription factors, PRC2-regulated Esrrg is a novel M-cell–specific transcription factor acting on a receptor activator of nuclear factor κB ligand–receptor activator of nuclear factor κB–induced nuclear factor-κB pathway, upstream of Sox8, and necessary but not sufficient for a mature M-cell marker of Gp2 expression. Conclusions: PRC2 regulates a significant set of genes in M cells including Esrrg, which is critical for M-cell development and differentiation. Loss of Esrrg led to an immature M-cell phenotype lacking in Sox8 and Gp2 expression. Transcript profiling: the data have been deposited in the NCBI Gene Expression Omnibus database (GSE157629).

AB - Background & Aims: Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer's patches (PPs) in the intestine and are responsible for monitoring and transcytosis of antigens, microorganisms, and pathogens. Mature M cells use the receptor glycoprotein 2 (GP2) to aid in transcytosis. Recent studies have shown transcription factors, Spi-B and SRY-Box Transcription Factor 8 (Sox8). are necessary for M-cell differentiation, but not sufficient. An exhaustive set of factors sufficient for differentiation and development of a mature GP2+ M cell remains elusive. Our aim was to understand the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M-cell development. Estrogen-related–receptor γ (Esrrg), identified as a PRC2-regulated gene, was studied in depth, in addition to its relationship with Spi-B and Sox8. Methods: Comparative chromatin immunoprecipitation and global run-on sequencing analysis of mouse intestinal organoids were performed in stem condition, enterocyte conditions, and receptor activator of nuclear factor κ B ligand–induced M-cell condition. Esrrg, which was identified as one of the PRC2-regulated transcription factors, was studied in wild-type mice and knocked out in intestinal organoids using guide RNA's. Sox8 null mice were used to study Esrrg and its relation to Sox8. Results: chromatin immunoprecipitation and global run-on sequencing analysis showed 12 novel PRC2 regulated transcription factors, PRC2-regulated Esrrg is a novel M-cell–specific transcription factor acting on a receptor activator of nuclear factor κB ligand–receptor activator of nuclear factor κB–induced nuclear factor-κB pathway, upstream of Sox8, and necessary but not sufficient for a mature M-cell marker of Gp2 expression. Conclusions: PRC2 regulates a significant set of genes in M cells including Esrrg, which is critical for M-cell development and differentiation. Loss of Esrrg led to an immature M-cell phenotype lacking in Sox8 and Gp2 expression. Transcript profiling: the data have been deposited in the NCBI Gene Expression Omnibus database (GSE157629).

KW - Esrrg

KW - Gut Immunity

KW - Microfold Cells

KW - PRC2

KW - RankL

U2 - 10.1016/j.jcmgh.2021.05.014

DO - 10.1016/j.jcmgh.2021.05.014

M3 - Article

C2 - 34058415

AN - SCOPUS:85111558689

SN - 2352-345X

VL - 12

SP - 873

EP - 889

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

IS - 3

ER -

Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development

Abstract

Funding

Keywords

Publication forum classification

ASJC Scopus subject areas

Access to Document

Fingerprint

Equipment

Adult Stem Cell Organoids Facility

Cite this