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Título: | PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification |
Autor: | Spaapen, Frank; Eijssen, Lars M. T.; Adriaens, Michiel E.; Welting, Tim J.; Prickaerts, Peggy; Salvaing, Juliette; Dahlmans, Vivian; Surtel, Donald A. M.; Kruitz, Frans; Kuijer, Roel; Takihara, Yoshihiro; Marks, Hendrik; Stunnenberg, Hendrik G.; Wouters, Bradly G.; Vidal, Miguel CSIC ORCID ; Voncken, Jan Willem | Fecha de publicación: | 11-dic-2017 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | Epigenomes 1(3): 22 (2017) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.3390/epigenomes1030022 | URI: | http://hdl.handle.net/10261/158511 | DOI: | 10.3390/epigenomes1030022 | E-ISSN: | 2075-4655 | Identificadores: | doi: 10.3390/epigenomes1030022 |
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