Our results are the first

Our results are the first to demonstrate that ERRγ acts as a catabolic regulator of cartilage degeneration and OA pathogenesis, and collectively support the idea that ERRγ could be a therapeutic target for OA
Introduction DNA cytosine-5-methyltransferases (Dnmts) catalyze the methyl transfer from S-adenosyl-l-methionine to the BET bromodomain inhibitor in CpG dinucleotides [1]. Gene silencing due to DNA hypermethylation of promoter regions is mainly controlled by three Dnmts (Dnmt1, Dnmt3α and Dnmt3b) [2]. Increased Dnmt expression has been reported in several human cancers, including human hepatocellular carcinoma (HCC) [3]. Despite evidence for their critical roles in carcinogenesis, limited information is available regarding how the expression of Dnmts are transcriptionally regulated [4], [5], [6], [7]. Understanding the molecular mechanisms controlling Dnmt expression is essential for learning how changes in DNA methylation result in or predispose to the development of liver cancer. Nuclear receptor small heterodimer partner (SHP, NROB2) is a transcriptional regulator of a number of genes that play critical roles in hepatic lipid metabolism [8], [9], [10], [11], [12]. Our recent studies show that SHP functions as a tumor suppressor in HCC. Deletion of the SHP gene promotes spontaneous hepatoma formation in mice due to hepatocyte hyperproliferation [13] and decreased apoptosis [14], and SHP expression is diminished in HCC in humans due to promoter hypermethylation [15]. These studies provide strong evidence for a critical role of SHP in hepatocarcinogenesis.
Materials and methods
Results
Discussion Previous work has shown that the dnmt1 promoter of mouse is independently activated by Sp1/Sp3 [4] and E2F [5], [25] transcription factors, and that human DNMT1 is activated by STAT3 [7]. A recent study demonstrated that p53 is a negative regulator of Dnmt1 promoter activity [26]. However, no information is available whether Dnmt1 gene transcription is regulated by nuclear receptors. Importantly, the co-recruitment of SHP with ERRγ to the dnmt1/DNMT1 promoters significantly decreased the enrichment of ERRγ. In addition, binding of ERRγ to the dnmt1 promoter induces transcriptionally active configuration of the promoter, which is reversed by co-expression of SHP. This suggests that the major mechanism for SHP inhibition of dnmt1 promoter activity is through alteration of local chromatin structure by ERRγ. SHP-mediated repression is not limited to the action of ERRγ, because SHP also decreases H4Ac occupancy which is not significantly affected by ERRγ. The results suggest that SHP may have a general function to keep the local chromatin configuration of its target genes in a repressive mode, which is consistent with its role as a universal transcriptional repressor [27]. Over sixty chromatin modifying enzymes have been identified [28], [29], and many of them are associated with post-translational modification of H3Ac, H4Ac, H3K4Me2, and H3K9Me2. It remains to be determined in future studies whether SHP and ERRγ are co-recruited to a multiprotein complex including proteins governing the post-translational modification of histones, and how this would regulate the gene transcription of Dnmt1. Overall, our findings are important because they link SHP function to DNA methylation at the molecular levels. Considering the importance of Dnmt1 in DNA methylation associated silencing of tumor suppressors [2], and the critical role of SHP in liver cancer progression [13], [14], [15], the identification of the regulatory role of SHP in controlling Dnmt1 expression improves our understanding of the epigenetic mechanisms governing the development of liver cancer.
Conflicts of interest
Acknowledgements
Introduction Fetal growth restriction (FGR) refers to the failure of a fetus to reach its growth potential as a result of various adverse factors. FGR is a common pregnancy complication that affects approximately 5–10% of all pregnancies and is the second leading cause of perinatal mortality [1]. FGR is associated with a higher incidence of fetal distress, preterm delivery, and serious neonatal complications. FGR also increases the risk of long-term neurological abnormalities, cardiovascular complications, and adult metabolic syndrome [2,3].