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

• Published in: eLife Vol. 8
• Main Authors: Agrawal Singh, Shuchi, Lerdrup, Mads, Gomes, Ana-Luisa R, van de Werken, Harmen JG, Vilstrup Johansen, Jens, Andersson, Robin, Sandelin, Albin, Helin, Kristian, Hansen, Klaus
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 23.01.2019; eLife Sciences Publications, Ltd
• Subjects: Acetylation; Biology; Cancer; Cell Differentiation - genetics; Cell Lineage - genetics; Chromatin - metabolism; Chromosomes and Gene Expression; developmental enhancer; Embryonic Development - genetics; Enhancer Elements, Genetic - genetics; Enhancers; Epigenesis, Genetic; Epigenetics; Event-related potentials; Gene expression; Gene loci; Genetic Loci; Genomes; histone H3 lysine 27 tri-methylation; Histones - metabolism; human mesenchymal stem cells; Humans; Hypothesis testing; Lysine - metabolism; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchyme; Methyltransferase; Mineralization; N-Methyltransferase; Nicotinamide; Nicotinamide N-methyltransferase; Nicotinamide N-Methyltransferase - genetics; Nicotinamide N-Methyltransferase - metabolism; Osteoblastogenesis; osteogenesis; Osteogenesis - genetics; PLZF; Polycomb group proteins; Polycomb proteins; Promoter Regions, Genetic; Promyelocytic Leukemia Zinc Finger Protein - genetics; Promyelocytic Leukemia Zinc Finger Protein - metabolism; Protein Binding; Proteins; RNA - genetics; Stem cells; Transcription factors; Transcriptome - genetics; Denmark; New York; Netherlands; United States > US; Copenhagen Denmark; developmental enhancer; histone H3 lysine 27 tri-methylation; human mesenchymal stem cells; ZBTB16; chromosomes; osteogenesis; PLZF; human; Polycomb proteins; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.40364

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.