TY - JOUR TI - PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells AU - Agrawal Singh, Shuchi AU - Lerdrup, Mads AU - Gomes, Ana-Luisa R AU - van de Werken, Harmen JG AU - Vilstrup Johansen, Jens AU - Andersson, Robin AU - Sandelin, Albin AU - Helin, Kristian AU - Hansen, Klaus A2 - Tyler, Jessica K A2 - Glass, Christopher K VL - 8 PY - 2019 DA - 2019/01/23 SP - e40364 C1 - eLife 2019;8:e40364 DO - 10.7554/eLife.40364 UR - https://doi.org/10.7554/eLife.40364 AB - 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. KW - human mesenchymal stem cells KW - histone H3 lysine 27 tri-methylation KW - osteogenesis KW - developmental enhancer KW - Polycomb proteins KW - PLZF KW - ZBTB16 KW - polycomb proteins JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -