PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification
AbstractTransit 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
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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.
Spaapen F, Eijssen LMT, Adriaens ME, Welting TJ, Prickaerts P, Salvaing J, Dahlmans VEH, Surtel DAM, Kruitz F, Kuijer R, Takihara Y, Marks H, Stunnenberg HG, Wouters BG, Vidal M, Voncken JW. PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification. Epigenomes. 2017; 1(3):22.Chicago/Turabian Style
Spaapen, Frank; Eijssen, Lars M.T.; Adriaens, Michiel E.; Welting, Tim J.; Prickaerts, Peggy; Salvaing, Juliette; Dahlmans, Vivian E.H.; Surtel, Donald A.M.; Kruitz, Frans; Kuijer, Roel; Takihara, Yoshihiro; Marks, Hendrik; Stunnenberg, Hendrik G.; Wouters, Bradly G.; Vidal, Miguel; Voncken, Jan W. 2017. "PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification." Epigenomes 1, no. 3: 22.
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