Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile

Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile


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Sepulveda H.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | Aguilar R.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | Bustos F.,Center for Genome RegulationSantiagoChile | van Zundert B.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | Montecino M.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile
Journal of Cellular Physiology | Year: 2016

Wharton's Jelly mesenchymal stem cells (WJ-MSCs) are an attractive potential source of multipotent stem cells for bone tissue replacement therapies. However, the molecular mechanisms involved in their osteogenic conversion are poorly understood. Particularly, epigenetic control operating at the promoter regions of the two master regulators of the osteogenic program, RUNX2/P57 and SP7 has not yet been described in WJ-MSCs. Via quantitative PCR profiling and chromatin immunoprecipitation (ChIP) studies, here we analyze the ability of WJ-MSCs to engage osteoblast lineage. In undifferentiated WJ-MSCs, RUNX2/P57 P1, and SP7 promoters are found deprived of significant levels of the histone post-translational marks that are normally associated with transcriptionally active genes (H3ac, H3K27ac, and H3K4me3). Moreover, the RUNX2 P1 promoter lacks two relevant histone repressive marks (H3K9me3 and H3K27me3). Importantly, RUNX2 P1 promoter is found highly enriched in the H3K4me1 mark, which has been shown recently to mediate gene repression of key regulatory genes. Upon induction of WJ-MSCs osteogenic differentiation, we found that RUNX2/P57, but not SP7 gene expression is strongly activated, in a process that is accompanied by enrichment of activating histone marks (H3K4me3, H3ac, and H3K27ac) at the P1 promoter region. Histone mark analysis showed that SP7 gene promoter is robustly enriched in epigenetic repressive marks that may explain its poor transcriptional response to osteoblast differentiating media. Together, these results point to critical regulatory steps during epigenetic control of WJ-MSCs osteogenic lineage commitment that are relevant for future applications in regenerative medicine. © 2016 Wiley Periodicals, Inc.


Medina M.A.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | Ugarte G.D.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | Vargas M.F.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | Avila M.E.,Center for Biomedical ResearchUniversidad Andres BelloSantiagoChile | And 3 more authors.
Journal of Cellular Physiology | Year: 2016

Two distantly located promoter regions regulate the dynamic expression of RUNX genes during development: distal P1 and proximal P2 promoters. We have recently described that β-catenin increases total Runx1 mRNA levels in human CD34+ hematopoietic progenitors and enhances spatial proximity with its translocation partner ETO. Here, we report that induction of Wnt/β-catenin signaling in HL60 and Jurkat leukemia-derived cell lines and CD34+ progenitors selectively activate the production of the longer distal P1-Runx1 mRNA isoform. Gain- and loss-of-function experiments revealed that the differential increase in P1-Runx1 expression is accomplished through a minimal β-catenin responsive region that includes a highly conserved TCF/LEF-binding element, located -20/-16bp upstream of the canonical distal P1-Runx1 transcription start site. We conclude that the distal P1-Runx1 promoter is a direct transcriptional target of Wnt/β-catenin signaling that may be important in normal hematopoiesis or its transition into malignant stem cells during the onset or progression of leukemia. © 2015 Wiley Periodicals, Inc.

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