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Elife. 2019 Jan 23;8. pii: e40364. doi: 10.7554/eLife.40364.

PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells.

Author information

1
Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2
Department of Hematology, Cambridge Institute for Medical Research and Welcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
3
Centre for Epigenetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Department of Cell Biology, University Medical Center, Rotterdam, The Netherlands.
5
Cancer Computational Biology Center, University Medical Center, Rotterdam, The Netherlands.
6
Department of Urology, University Medical Center, Rotterdam, The Netherlands.
7
Department of Biology, The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark.
8
The Novo Nordisk Center for Stem Cell Biology, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark.
9
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
10
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States.

Abstract

The PLZF transcription factor is essential for osteogenic differentiation of hMSCs; however, its regulation and molecular function during this process is not fully understood. Here, we revealed that the ZBTB16 locus encoding PLZF, is repressed by Polycomb (PcG) and H3K27me3 in naive hMSCs. At the pre-osteoblast stage of differentiation, the locus lost PcG binding and H3K27me3, gained JMJD3 recruitment, and H3K27ac resulting in high expression of PLZF. Subsequently, PLZF was recruited to osteogenic enhancers, influencing H3K27 acetylation and expression of nearby genes important for osteogenic function. Furthermore, we identified a latent enhancer within the ZBTB16/PLZF locus itself that became active, gained PLZF, p300 and Mediator binding and looped to the promoter of the nicotinamide N-methyltransferase (NNMT) gene. The increased expression of NNMT correlated with a decline in SAM levels, which is dependent on PLZF and is required for osteogenic differentiation.

KEYWORDS:

PLZF; Polycomb proteins; ZBTB16; chromosomes; developmental enhancer; gene expression; histone H3 lysine 27 tri-methylation; human; human mesenchymal stem cells; osteogenesis; polycomb proteins

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