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Epigenomes 2017, 1(3), 22; https://doi.org/10.3390/epigenomes1030022

PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification

1
Department of Molecular Genetics , Maastricht University Medical Center, Universiteitssingel 50-60, 6229ER Maastricht, The Netherlands
2
Department of Bioinformatics (BiGCaT), Maastricht University Medical Center, Universiteitssingel 50-60, 6229ER Maastricht, The Netherlands
3
Maastricht Centre for Systems Biology—MaCSBio, Maastricht University Medical Center, Universiteitssingel 50-60, 6229ER Maastricht, The Netherlands
4
Department of Orthopedic Research, Maastricht University Medical Center, Universiteitssingel 50-60, 6229ER Maastricht, The Netherlands
5
Laboratoire de Physiologie Cellulaire et Végétale (LPCV), UMR 1417 INRA/UMR 5168 CNRS-CEA-UGA, Bioscience and Biotechnology Institute of Grenoble (BIG), Commissariat à l’Energie Atomique et aux Energies Renouvelables (CEA); 38054 Grenoble CEDEX 9, France
6
Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Deusinglaan 1, 9713AV Groningen, The Netherlands
7
Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
8
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Geert Grooteplein 28, 6525GA Nijmegen, The Netherlands
9
Maastricht Radiation Oncology (MaastRO) Laboratory, Maastricht University Medical Center, Universiteitssingel 50-60, 6229ER Maastricht, The Netherlands
10
Medical Biophysics and Radiation Oncology, Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada
11
Department of Cell and Molecular Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006 Madrid, Spain
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Luciano Di Croce
Received: 3 October 2017 / Revised: 24 November 2017 / Accepted: 24 November 2017 / Published: 11 December 2017
(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)
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Abstract

Transit amplification (TA), a state of combined, rapid proliferative expansion and differentiation of stem cell-descendants, remains poorly defined at the molecular level. The Polycomb Repressive Complex 1 (PRC1) protein BMI1 has been localized to TA compartments, yet its exact role in TA is unclear. PRC1 proteins control gene expression, cell proliferation and DNA-damage repair. Coordination of such DNA-templated activities during TA is predicted to be crucial to support DNA replication and differentiation-associated transcriptional programming. We here examined whether chondrogenesis provides a relevant biological context for synchronized coordination of these chromatin-based tasks by BMI1. Taking advantage of a prominently featuring TA-phase during chondrogenesis in vitro and in vivo, we here report that TA is completely dependent on intact PRC1 function. BMI1-depleted chondrogenic progenitors rapidly accumulate double strand DNA breaks during DNA replication, present massive non-H3K27me3-directed transcriptional deregulation and fail to undergo chondrogenic TA. Genome-wide accumulation of Topoisomerase 2α and Geminin suggests a model in which PRC1 synchronizes replication and transcription during rapid chondrogenic progenitor expansion. Our combined data reveals for the first time a vital cell-autonomous role for PRC1 during chondrogenesis. We provide evidence that chondrocyte hyper-replication and hypertrophy represent a unique example of programmed senescence in vivo. These findings provide new perspectives on PRC1 function in development and disease. View Full-Text
Keywords: polycomb; topoisomerase; transit amplification; chromatin; DNA replication; transcription; chondrogenesis; differentiation; DNA damage; hypertrophy; senescence polycomb; topoisomerase; transit amplification; chromatin; DNA replication; transcription; chondrogenesis; differentiation; DNA damage; hypertrophy; senescence
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Spaapen, F.; Eijssen, L.M.T.; Adriaens, M.E.; Welting, T.J.; Prickaerts, P.; Salvaing, J.; Dahlmans, V.E.H.; Surtel, D.A.M.; Kruitz, F.; Kuijer, R.; Takihara, Y.; Marks, H.; Stunnenberg, H.G.; Wouters, B.G.; Vidal, M.; Voncken, J.W. PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification. Epigenomes 2017, 1, 22.

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