The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis

F. Saapen, G.G.H. van den Akker, M.M.J. Caron, P. Prickaerts, C. Rofel, V.E.H. Dahlmans, D.A.M. Surtel, Y. Paulis, F. Schweizer, T.J.M. Welting, L.M. Eijssen, J.W. Voncken

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)

Abstract

Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.

Original languageEnglish
Article number58083
Number of pages16
JournalPLOS ONE
Volume8
Issue number3
DOIs
Publication statusPublished - 6 Mar 2013

Keywords

  • ONCOGENE-INDUCED SENESCENCE
  • ZINC-FINGER PROTEINS
  • EMBRYONIC STEM-CELLS
  • TRANSCRIPTION FACTORS
  • GROWTH-PLATE
  • HISTONE H3
  • SKELETAL DEVELOPMENT
  • NGFI-A
  • CHONDROCYTE DIFFERENTIATION
  • BIOLOGICAL PATHWAYS

Cite this

@article{3715326b70a44bbba10b6d63511d674b,
title = "The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis",
abstract = "Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.",
keywords = "ONCOGENE-INDUCED SENESCENCE, ZINC-FINGER PROTEINS, EMBRYONIC STEM-CELLS, TRANSCRIPTION FACTORS, GROWTH-PLATE, HISTONE H3, SKELETAL DEVELOPMENT, NGFI-A, CHONDROCYTE DIFFERENTIATION, BIOLOGICAL PATHWAYS",
author = "F. Saapen and {van den Akker}, G.G.H. and M.M.J. Caron and P. Prickaerts and C. Rofel and V.E.H. Dahlmans and D.A.M. Surtel and Y. Paulis and F. Schweizer and T.J.M. Welting and L.M. Eijssen and J.W. Voncken",
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language = "English",
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journal = "PLOS ONE",
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The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis. / Saapen, F.; van den Akker, G.G.H.; Caron, M.M.J.; Prickaerts, P.; Rofel, C.; Dahlmans, V.E.H.; Surtel, D.A.M.; Paulis, Y.; Schweizer, F.; Welting, T.J.M.; Eijssen, L.M.; Voncken, J.W.

In: PLOS ONE, Vol. 8, No. 3, 58083, 06.03.2013.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis

AU - Saapen, F.

AU - van den Akker, G.G.H.

AU - Caron, M.M.J.

AU - Prickaerts, P.

AU - Rofel, C.

AU - Dahlmans, V.E.H.

AU - Surtel, D.A.M.

AU - Paulis, Y.

AU - Schweizer, F.

AU - Welting, T.J.M.

AU - Eijssen, L.M.

AU - Voncken, J.W.

PY - 2013/3/6

Y1 - 2013/3/6

N2 - Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.

AB - Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.

KW - ONCOGENE-INDUCED SENESCENCE

KW - ZINC-FINGER PROTEINS

KW - EMBRYONIC STEM-CELLS

KW - TRANSCRIPTION FACTORS

KW - GROWTH-PLATE

KW - HISTONE H3

KW - SKELETAL DEVELOPMENT

KW - NGFI-A

KW - CHONDROCYTE DIFFERENTIATION

KW - BIOLOGICAL PATHWAYS

U2 - 10.1371/journal.pone.0058083

DO - 10.1371/journal.pone.0058083

M3 - Article

VL - 8

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 3

M1 - 58083

ER -