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PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification
- Source :
- Epigenomes, Vol 1, Iss 3, p 22 (2017)
- Publication Year :
- 2017
- Publisher :
- MDPI AG, 2017.
-
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.
Details
- Language :
- English
- ISSN :
- 20754655
- Volume :
- 1
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- Epigenomes
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.b4b3f61c4d34a93b35991f74ff5772b
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/epigenomes1030022