PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells
File(s)
Published version
Author(s)
Agrawal Singh, Shuchi
Lerdrup, Mads
Gomes, Ana-Luisa R
van de Werken, Harmen JG
Vilstrup Johansen, Jens
Type
Journal Article
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.
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.
Date Issued
2019-01-23
Date Acceptance
2018-12-13
Citation
eLife, 2019, 8
ISSN
2050-084X
Publisher
eLife Sciences Publications Ltd
Journal / Book Title
eLife
Volume
8
Copyright Statement
© 2019, Agrawal Singh et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
License URL
Publication Status
Published
Article Number
e40364
Date Publish Online
2019-01-23