期刊
GENE
卷 550, 期 1, 页码 1-9出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.gene.2014.05.044
关键词
Osteoblast differentiation; Runx2-P1; Gene regulation; DNase hypersensitivity; Histone modification
资金
- National Institutes of Health [P01 CA082834, P01 AR48818, R01 AR039588, R37 DE012528]
Runx2 is a developmentally regulated gene in vertebrates and is essential for bone formation and skeletal homeostasis. The induction of runx2-P1 isoform transcripts is a hallmark of early osteoblastogenesis. Although previous in vitro studies have defined a minimal Runx2-P1 promoter sequence with well-characterized functional elements, several lines of evidence suggest that transcription of the Runx2-P1 isoform relies on elements that extend beyond the previously defined P1 promoter boundaries. In this study, we examined Runx2-P1 transcriptional regulation in a cellular in vivo context during early osteoblastogenesis of MC3T3-E1 cultures and BMSCs induced towards the bone lineage by multi-layered analysis of the Runx2-P1 gene promoter using the following methodologies: 1) sequence homology among several mammalian species, 2) DNasel hypersensitivity coupled with massively parallel sequencing (DNase-seq), and 3) chromatin immunoprecipitation of activating histone modifications coupled with massively parallel sequencing (ChIP-seq). These epigenetic features have allowed the demarcation of boundaries that redefine the minimal Runx2-P1 promoter to include a 336-bp sequence that mediates responsiveness to osteoblast differentiation. We also find that an additional level of control is contributed by a regulatory region in the 5'-UTR of Runx2-P1. (C) 2014 Elsevier B.V. All rights reserved.
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