Epigenetic silencing of HDAC1 by miR-449a upregulates Runx2 and promotes osteoblast differentiation

Abstract

Human-induced pluripotent (iPS) cells can be induced to differentiate into osteoblasts, but the process is inefficient and time-consuming. Previous studies indicated a close association between the expression of Runx2 and osteoblast differentiation, and established that the transcriptional activation of the Runx2 gene was closely associated with histone acetylation. microRNA-449a (miR-449a) represses HDAC1 expression, thereby regulating histone acetylation. In the present study, whether the expression of miR-449a enhanced the generation of osteoblasts from human iPS cells was investigated. Introduction of miR-449a into human iPS cells resulted in the expression of osteoblast markers after only four days, compared to eight days for untransfected human iPS cells. Differentiation to osteoblasts was associated with a reduction in HDAC1 expression, and higher levels of histone acetylation, particularly at the binding sites on the Runx2 promoter in the human miR-449a-transfected iPS cells. Silencing of endogenous HDAC1 expression by exogenous miR-449a therefore maintains histone acetylation status, stimulates Runx2 gene expression and rapidly promotes osteoblast differentiation.

TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts

“…Expression of class I HDACs (HDAC1, -2 and -3) has been reported to negatively correlate with the expression the key osteogenic transcription factor Runx2 [20][21][22]. In our group, we could show that the upregulation of HDAC6 results in shortened and deformed primary cilia, which impairs the mechanically driven osteogenesis [27].…”

“…Improved osteogenic differentiation by using small chemical inhibitors for HDACs [16,18] points towards a direct acetylation-dependent mechanism. This is described for HDAC1 and -3 overexpression, which inhibits the expression of the key osteogenic transcription factor Runx2 [20][21][22]. Furthermore, the overexpression of HDAC6 causes a de-acetylation of α-tubulin, resulting in damaged primary cilia and impaired mechanically driven osteogenesis [27].…”

“…There is evidence that several HDACs affect the expression and activity of the key osteogenic transcription factor Runx2. Runx2 expression is shown to be inhibited by HDAC1 and HDAC3 [20][21][22]. Runx2 transcriptional activity is reduced by the binding of class II HDACs (HDAC4, -5, -6, and -7) to Runx2 [23][24][25][26].…”

MicroRNAs in neuroblastoma differentiation and differentiation therapy

“…miR-449a has been found to induce differentiation of other cell types. Liu et al ectopically expressed miR-449a in vitro in pluripotent cells, and detected osteoblast differentiation markers after several days [52] . The differentiation of these cells was correlated with the down-regulation of HDAC1, a direct target of miR-449a [52] .…”

“…Liu et al ectopically expressed miR-449a in vitro in pluripotent cells, and detected osteoblast differentiation markers after several days [52] . The differentiation of these cells was correlated with the down-regulation of HDAC1, a direct target of miR-449a [52] . A study done by Capuano et al suggested that miR-449a may also be involved in the differentiation of intestinal cells [53] .…”