Thus, the objective of this study was to determine the expression profile of PHF20 during osteoblast differentiation and alteration of the PHF20 effects by overexpressing or inhibiting PHF20. However, the role of PHF20 in osteoblast differentiation has not been reported yet. Overall, the lack of PHF20 had led to abnormal development of skeletal formation in mice. Bone density analysis through microCT has shown that PHF20 KO mice have lower skeleton level compared to WT mice 15. In addition, it has been reported that PHF20 knock-out (KO) mouse has a weak skeleton with lumbar vertebrae missing 15. PHF20 affects cell growth, differentiation, and survival through epigenetic modification of the target gene 16. PHD finger domain can recognize H3K4me2 residues and affect its methylation along with mixed lineage leukemia 1 (MLL1)-lysine methyltransferase (KMT) complex 16, 20. PHF20 is involved in histone 4 lysine 16 (H4K16) acetylation as a member of the MOF-NSL complex. In addition, PHF20 acts as a methylation effector that contributes to the up-regulation of p53 in response to DNA damage, and thereby plays a role in the activation and stabilization of p53 protein 16, 19. Recent studies have shown that the second Tudor domain of PHF20 is dimerized and binds directly to p53K370me2 and p53K382me2, which enhances the binding of PHF20 to p53. PHF20 has two types of domains (two N-terminal Tudor domains and one C-terminal PHD finger domain) that can bind methylated residues 18. It is also a component of males absent on the first (MOF)-nonspecific lethal (NSL) lysine acetyltransferase complex involved in the acetylation of histone and non-histone proteins 15, 16, 17. ![]() Plant homeodomain finger protein 20 (PHF20) has multiple domains. ![]() While, methylation of histone 3 lysine 9 (H3K9) and histone 3 lysine 27 (H3K27) inhibited the gene activity 14. Osteoblast specific gene transcription and differentiation are activated by methylation or acetylation of histone 3 lysine 4 (H3K4). In general, histone modification is catalyzed by several PTM enzymes such as histone methyltransferases (HMTases) and histone acetyltransferases (HATases) with completely different transcriptional outputs and biological functions depending on the specific genomic loci or chromosomal domains beyond protein expression according to nucleotide sequence 12, 13. The production of Runx2 transcript in osteoblast differentiation is affected by various post-translational modifications (PTMs) of histone, including methylation, acetylation, and phosphorylation 10, 11. It is active in mature osteoblasts and hypertrophic chondrocytes 9. Runx2 P1 promoter transcript is more relevant to bone than the P2 promoter. The production of Runx2-II and Runx2-I is controlled by a distal promoter (P1) and a proximal promoter (P2), respectively 8. They have different amino terminal sequences. Runx2 has two isoforms: Runx2-II and Runx2-I. Runx2 null mice are found to have defects in skeletal formation due to maturational arrest of osteoblast differentiation 5, 7. Mutation of Runx2 can result in the formation of skeletal parts such as cleidocranial dysplasia 5, 6. Transcriptional factor runt-related transcription factor 2 (Runx2) is a key regulator of osteoblast differentiation 1, 2, 3, 4. Osteoblast differentiation and bone formation are regulated by a number of extracellular molecules such as bone morphogenetic protein 2 (BMP2), transcriptional factors, and posttranslational modifiers. Taken together, these results indicate that methyl lysine-binding protein PHF20 might be a novel regulator of osteoblast differentiation. ![]() Overexpression of PHF20 restored the Bix-01294 effects. Interestingly, Bix-01294, a histone methylation inhibitor, decreased mineralized nodule formation through decreasing the levels of H3K4me3 and Runx2. Moreover, PHF20 increased the enrichment of H3K4me3 on the promoter of Runx2 followed by increased Runx2 promoter activity. Mechanistically, PHF20 increased the promoter activity of osteogenic genes including Og2, Alp, and Bsp through direct association with Runx2. In contrast, inhibition of PHF20 expression reduced osteoblast differentiation and mineralization. Overexpression of PHF20 enhanced ALP activity and mineralized nodule formation as well as the expression of osteogenic markers including Runx2. Expression of PHF20 was gradually increased during osteoblast differentiation. The objective of this study was to determine the role of PHF20 in osteoblast differentiation and mineralization. However, the molecular basis of PHF20 involved in skeletal development has not been elucidated yet. Global deletion of PHF20 has shown spinal bone defects and reduced skeletal formation. Plant homeodomain finger protein 20 (PHF20), a methyl lysine effector protein, is a component MOF-NSL lysine acetyltranferase complex.
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