YY2 Promotes Osteoblast Differentiation by Upregulating Osterix Transcriptional Activity

Abstract

Yin Yang 2 (YY2) is a paralog of YY1, a well-known multifunctional transcription factor containing a C-terminal zinc finger domain. Although the role of YY1 in various biological processes, such as the cell cycle, cell differentiation and tissue development, is well established, the function of YY2 has not been fully determined. In this study, we investigated the functional role of YY2 during osteoblast differentiation. YY2 overexpression and knockdown increased and decreased osteoblast differentiation, respectively, in BMP4-induced C2C12 cells. Mechanistically, YY2 overexpression increased the mRNA and protein levels of Osterix (Osx), whereas YY2 knockdown had the opposite effect. To investigate whether YY2 regulates Osx transcription, the effect of YY2 overexpression and knockdown on Osx promoter activity was evaluated. YY2 overexpression significantly increased Osx promoter activity in a dose-dependent manner, whereas YY2 knockdown had the opposite effect. Furthermore, vectors containing deletion and point mutations were constructed to specify the regulation site. Both the Y1 and Y2 sites were responsible for YY2-mediated Osx promoter activation. These results indicate that YY2 is a positive regulator of osteoblast differentiation that functions by upregulating the promoter activity of Osx, a representative osteogenic transcription factor in C2C12 cells.

Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis

“…A recent study has validated that Yy2 could promote osteoblast differentiation by upregulating transcriptional activity of Osterix in BMP4-induced C2C12 cells. 39 Consistently, we detected significantly lower expression of Yy2 in osteoporosis mice and experimentally verified putative contributory roles of YY2 in promoting human osteoblast differentiation. The roles of YY2 in chromatin organization are currently unknown.…”

“…We noted that many enriched TFs had known roles in osteoblast differentiation or bone metabolism ( Figure 4 A; Table S13 ), such as HOXC10, 37 MEF2A, 38 or YY2. 39 Consistently, GO biological process enrichment analysis revealed that enriched TFs were significantly enriched for several bone-relevant pathways including skeletal system development and ossification ( Figure 4 C). To further explore putative roles in osteoblast differentiation for enriched TFs, we compared their expression change in differentiated osteoblast for different time points (0.5–96 h) against non-differentiated cells ( Table S1 ), 40 and we detected 10 TFs (CPEB1, ETS1, FOXC2, FOXD2, HOXC10, MEF2A, NFE2L3, SMAD4, SOX9, and YY1) with significantly changed expression (FDR < 0.05, Table S14 ).…”

“…In contrast, the second top-ranked TF, YY2 (score = 5.33, Table S15 ) had been validated to play positive roles in promoting osteoblast differentiation by upregulating transcription activity of Osx. 39 The third top-scored TF, YY1 (score = 5.01, Table S15 ), was a homolog of YY2 and acts as a known critical structural regulator of active enhancer-promoter loop formation. 42 …”

The Osteogenesis Mechanisms of Dental Alveolar Bone Socket Post Induction with Hydroxyapatite Bovine Tooth Graft: An Animal Experimental in Rattus norvegicus Strain Wistar

“…The previous study also showed the differentiation of OB via upregulating RUNX2 34,35 and OSX's role as an inducer. 30,36 The increase of OB is followed by increasing OCN. OCN may function as a matrix signal in the recruitment and differentiation of bone-resorbing cells.…”