Histone Modifiers, YY1 and p300, Regulate the Expression of Cartilage-specific Gene, Chondromodulin-I, in Mesenchymal Stem Cells

Abstract

Elucidating the regulatory mechanism for tissue-specific gene expression is key to understanding the differentiation process. The chondromodulin-I gene (ChM-I) is a cartilage-specific gene, the expression of which is regulated by the transcription factor, Sp3. The binding of Sp3 to the core-promoter region is regulated by the methylation status of the Sp3-binding motif as we reported previously. In this study, we have investigated the molecular mechanisms of the down-regulation of ChM-I expression in mesenchymal stem cells (MSCs) and normal mesenchymal tissues other than cartilage. The core-promoter region of cells in bone and peripheral nerve tissues was hypermethylated, whereas the methylation status in cells of other tissues including MSCs did not differ from that in cells of cartilage, suggesting the presence of inhibitory mechanisms other than DNA methylation. We found that a transcriptional repressor, YY1, negatively regulated the expression of ChM-I by recruiting histone deacetylase and thus inducing the deacetylation of associated histones. As for a positive regulator, we found that a transcriptional co-activator, p300, bound to the core-promoter region with Sp3, inducing the acetylation of histone. Inhibition of YY1 in combination with forced expression of p300 and Sp3 restored the expression of ChM-I in cells with a hypomethylated promoter region, but not in cells with hypermethylation. These results suggested that the expression of tissue-specific genes is regulated in two steps; reversible down-regulation by transcriptional repressor complex and tight down-regulation via DNA methylation.

Yin Yang 1 is a multi-functional regulator of adipocyte differentiation in 3T3-L1 cells

“…Other group revealed that YY1 as a potential cofactor for Hdm2 in the regulation of p53 degradation (Sui et al, 2004). On the contrary, It has been clarified that YY1 represses chondrocyte (Aoyama et al, 2010a), myoblast (MacLellan et al, 1994 and osteoblast differentiation (Jeong et al, 2014). Our result data showing that YY1 inhibits adipocyte differentiation.…”

“…This intrinsic factor is important in cell differentiation by regulating gene expression. It regulates chondrocyte differentiation from mesenchymal stem cells by regulating the expression of cartilage-specific genes (Aoyama et al, 2010b). Additionally, YY1 represses myoblast differentiation by blocking muscle-specific genes such as those for smooth muscle, skeletal, and cardiac aactin (MacLellan et al, 1994).…”

Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory

“…The most enriched motif was Yin Yang1 (YY1) (Extended Data Fig. 3o; YY1, p = 1e-599) which recruits the two acetyl-CoA-dependent HAT enzymes CREB-binding protein (CBP) and E1A binding protein (p300) 17 , consistent with ACSS2 fueling nearby catalytic HAT activity.…”

The Oncogenic Role of Yin Yang 1

“…49 Recently, YY1 was shown to repress expression of the KiSS1 and chondromodulin-I genes, which inhibit tumor metastasis and angiogenesis, respectively. 66,67 YY1 also down-regulates death receptor (DR) 5, a key component in the extrinsic pathway of apoptosis, and consequently confers therapeutic resistance to tumor cells. 68 In hepatocellular carcinoma, overexpressed YY1 negatively correlates with Raf kinase inhibitor protein (RKIP), a metastasis-suppressor.…”