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 -