Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells

The polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem cells and their progeny. PRC2 helps to maintain adult stem cell populations, but little is known about its functions in intestinal stem cells....

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Vydáno v:Gastroenterology (New York, N.Y. 1943) Ročník 151; číslo 4; s. 684 - 697.e12
Hlavní autoři: Koppens, Martijn A J, Bounova, Gergana, Gargiulo, Gaetano, Tanger, Ellen, Janssen, Hans, Cornelissen-Steijger, Paulien, Blom, Marleen, Song, Ji-Ying, Wessels, Lodewyk F A, van Lohuizen, Maarten
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.10.2016
Témata:
Adult Stem Cells - physiology
Animals
Base Sequence
Cell Differentiation
Cell Lineage
Cell Proliferation
Chromatin Immunoprecipitation
Enhancer of Zeste Homolog 2 Protein - deficiency
Intestines - cytology
Intestines - metabolism
Mice
Mice, Knockout
Polycomb Repressive Complex 2 - deficiency
Polycomb Repressive Complex 2 - genetics
Wnt Signaling Pathway
Development
ISC
PRC1
Small Intestine
ISSN:1528-0012
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Abstract The polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem cells and their progeny. PRC2 helps to maintain adult stem cell populations, but little is known about its functions in intestinal stem cells. We studied phenotypes of mice with intestine-specific deletion of the PRC2 proteins embryonic ectoderm development (EED) (a subunit required for PRC2 function) and enhancer of zeste homolog 2 (EZH2) (a histone methyltransferase). We performed studies of AhCre;EedLoxP/LoxP (EED knockout) mice and AhCre;Ezh2LoxP/LoxP (EZH2 knockout) mice, which have intestine-specific disruption in EED and EZH2, respectively. Small intestinal crypts were isolated and subsequently cultured to grow organoids. Intestines and organoids were analyzed by immunohistochemical, in situ hybridization, RNA sequence, and chromatin immunoprecipitation methods. Intestines of EED knockout mice had massive crypt degeneration and lower numbers of proliferating cells compared with wild-type control mice. Cdkn2a became derepressed and we detected increased levels of P21. We did not observe any differences between EZH2 knockout and control mice. Intestinal crypts from EED knockout mice had signs of aberrant differentiation of uncommitted crypt cells-these differentiated toward the secretory cell lineage. Furthermore, crypts from EED-knockout mice had impaired Wnt signaling and concomitant loss of intestinal stem cells, this phenotype was not reversed upon ectopic stimulation of Wnt and Notch signaling in organoids. Analysis of gene expression patterns from intestinal tissues of EED knockout mice showed dysregulation of several genes involved in Wnt signaling. Wnt signaling was regulated directly by PRC2. In intestinal tissues of mice, PRC2 maintains small intestinal stem cells by promoting proliferation and preventing differentiation in the intestinal stem cell compartment. PRC2 controls gene expression in multiple signaling pathways that regulate intestinal homeostasis. Sequencing data are available in the genomics data repository GEO under reference series GSE81578; RNA sequencing data are available under subseries GSE81576; and ChIP sequencing data are available under subseries GSE81577.
AbstractList BACKGROUND & AIMSThe polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem cells and their progeny. PRC2 helps to maintain adult stem cell populations, but little is known about its functions in intestinal stem cells. We studied phenotypes of mice with intestine-specific deletion of the PRC2 proteins embryonic ectoderm development (EED) (a subunit required for PRC2 function) and enhancer of zeste homolog 2 (EZH2) (a histone methyltransferase).METHODSWe performed studies of AhCre;EedLoxP/LoxP (EED knockout) mice and AhCre;Ezh2LoxP/LoxP (EZH2 knockout) mice, which have intestine-specific disruption in EED and EZH2, respectively. Small intestinal crypts were isolated and subsequently cultured to grow organoids. Intestines and organoids were analyzed by immunohistochemical, in situ hybridization, RNA sequence, and chromatin immunoprecipitation methods.RESULTSIntestines of EED knockout mice had massive crypt degeneration and lower numbers of proliferating cells compared with wild-type control mice. Cdkn2a became derepressed and we detected increased levels of P21. We did not observe any differences between EZH2 knockout and control mice. Intestinal crypts from EED knockout mice had signs of aberrant differentiation of uncommitted crypt cells-these differentiated toward the secretory cell lineage. Furthermore, crypts from EED-knockout mice had impaired Wnt signaling and concomitant loss of intestinal stem cells, this phenotype was not reversed upon ectopic stimulation of Wnt and Notch signaling in organoids. Analysis of gene expression patterns from intestinal tissues of EED knockout mice showed dysregulation of several genes involved in Wnt signaling. Wnt signaling was regulated directly by PRC2.CONCLUSIONSIn intestinal tissues of mice, PRC2 maintains small intestinal stem cells by promoting proliferation and preventing differentiation in the intestinal stem cell compartment. PRC2 controls gene expression in multiple signaling pathways that regulate intestinal homeostasis. Sequencing data are available in the genomics data repository GEO under reference series GSE81578; RNA sequencing data are available under subseries GSE81576; and ChIP sequencing data are available under subseries GSE81577.
The polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem cells and their progeny. PRC2 helps to maintain adult stem cell populations, but little is known about its functions in intestinal stem cells. We studied phenotypes of mice with intestine-specific deletion of the PRC2 proteins embryonic ectoderm development (EED) (a subunit required for PRC2 function) and enhancer of zeste homolog 2 (EZH2) (a histone methyltransferase). We performed studies of AhCre;EedLoxP/LoxP (EED knockout) mice and AhCre;Ezh2LoxP/LoxP (EZH2 knockout) mice, which have intestine-specific disruption in EED and EZH2, respectively. Small intestinal crypts were isolated and subsequently cultured to grow organoids. Intestines and organoids were analyzed by immunohistochemical, in situ hybridization, RNA sequence, and chromatin immunoprecipitation methods. Intestines of EED knockout mice had massive crypt degeneration and lower numbers of proliferating cells compared with wild-type control mice. Cdkn2a became derepressed and we detected increased levels of P21. We did not observe any differences between EZH2 knockout and control mice. Intestinal crypts from EED knockout mice had signs of aberrant differentiation of uncommitted crypt cells-these differentiated toward the secretory cell lineage. Furthermore, crypts from EED-knockout mice had impaired Wnt signaling and concomitant loss of intestinal stem cells, this phenotype was not reversed upon ectopic stimulation of Wnt and Notch signaling in organoids. Analysis of gene expression patterns from intestinal tissues of EED knockout mice showed dysregulation of several genes involved in Wnt signaling. Wnt signaling was regulated directly by PRC2. In intestinal tissues of mice, PRC2 maintains small intestinal stem cells by promoting proliferation and preventing differentiation in the intestinal stem cell compartment. PRC2 controls gene expression in multiple signaling pathways that regulate intestinal homeostasis. Sequencing data are available in the genomics data repository GEO under reference series GSE81578; RNA sequencing data are available under subseries GSE81576; and ChIP sequencing data are available under subseries GSE81577.
Author Wessels, Lodewyk F A
van Lohuizen, Maarten
Koppens, Martijn A J
Gargiulo, Gaetano
Tanger, Ellen
Song, Ji-Ying
Bounova, Gergana
Cornelissen-Steijger, Paulien
Blom, Marleen
Janssen, Hans
Author_xml – sequence: 1
  givenname: Martijn A J
  surname: Koppens
  fullname: Koppens, Martijn A J
  organization: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
– sequence: 2
  givenname: Gergana
  surname: Bounova
  fullname: Bounova, Gergana
  organization: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  givenname: Gaetano
  surname: Gargiulo
  fullname: Gargiulo, Gaetano
  organization: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  givenname: Ellen
  surname: Tanger
  fullname: Tanger, Ellen
  organization: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
– sequence: 5
  givenname: Hans
  surname: Janssen
  fullname: Janssen, Hans
  organization: Division of Cell Biology II, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  givenname: Paulien
  surname: Cornelissen-Steijger
  fullname: Cornelissen-Steijger, Paulien
  organization: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  givenname: Marleen
  surname: Blom
  fullname: Blom, Marleen
  organization: Transgenic Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
– sequence: 8
  givenname: Ji-Ying
  surname: Song
  fullname: Song, Ji-Ying
  organization: Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
– sequence: 9
  givenname: Lodewyk F A
  surname: Wessels
  fullname: Wessels, Lodewyk F A
  organization: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, The Netherlands; Cancer Genomics Centre Netherlands, Utrecht, The Netherlands
– sequence: 10
  givenname: Maarten
  surname: van Lohuizen
  fullname: van Lohuizen, Maarten
  email: M.V.Lohuizen@NKI.NL
  organization: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Cancer Genomics Centre Netherlands, Utrecht, The Netherlands. Electronic address: M.V.Lohuizen@NKI.NL
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27342214$$D View this record in MEDLINE/PubMed
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Snippet The polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem...
BACKGROUND & AIMSThe polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing...
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SubjectTerms Adult Stem Cells - physiology
Animals
Base Sequence
Cell Differentiation
Cell Lineage
Cell Proliferation
Chromatin Immunoprecipitation
Enhancer of Zeste Homolog 2 Protein - deficiency
Intestines - cytology
Intestines - metabolism
Mice
Mice, Knockout
Polycomb Repressive Complex 2 - deficiency
Polycomb Repressive Complex 2 - genetics
Wnt Signaling Pathway
Title Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells
URI https://www.ncbi.nlm.nih.gov/pubmed/27342214
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