Search

DNA cytosine methylation plays a vital role in repressing retrotransposons, and such derepression is linked with developmental failure, tumorigenesis and aging. DNA methylation patterns are formed by precisely regulated actions of DNA methylation writers (DNA methyltransferases) and erasers (TET, ten-eleven translocation dioxygenases). However, the mechanisms underlying target-specific oxidation of 5mC by TET dioxygenases remain largely unexplored. Here we show that a large low-complexity domain (LCD), located in the catalytic part of Tet enzymes, negatively regulates the dioxygenase activity. Recombinant Tet3 lacking LCD is shown to be hyperactive in converting 5mC into oxidized species in vitro. Endogenous expression of the hyperactive Tet3 mutant in mouse oocytes results in genome-wide 5mC oxidation. Notably, the occurrence of aberrant 5mC oxidation correlates with a consequent loss of the repressive histone mark H3K9me3 at ERVK retrotransposons. The erosion of both 5mC and H3K9me3 causes ERVK derepression along with upregulation of their neighboring genes, potentially leading to the impairment of oocyte development. These findings suggest that Tet dioxygenases use an intrinsic auto-regulatory mechanism to tightly regulate their enzymatic activity, thus achieving spatiotemporal specificity of methylome reprogramming, and highlight the importance of methylome integrity for development. Here the authors show that TET dioxygenases, the erasers of DNA methylation, use a self-limiting mechanism via their LCD domain to ensure adaptable methylome status and protect the genome from excessive oxidative methylation.

Yanhong Ding,1,* Cheng Pu,2,* Xiao Zhang,3 Gaoyan Tang,1 Fengjuan Zhang,3 Guohua Yu1 1Department of Medical Oncology, the First Affiliated Hospital of Weifang Medical University, Weifang, 261032, People’s Republic of China; 2Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, 611130, People’s Republic of China; 3Department of Microbiology, Weifang Center for Disease Control and Prevention, Weifang, 261061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guohua Yu, Email ghyry@126.comPurpose: HIV-infected immunological non-responders (INRs) failed to achieve the normalization of CD4+ T cell counts despite their undetectable viral load. INRs have an increased risk of clinical progressions of Acquired Immunodeficiency Syndrome (AIDS) and non-AIDS events, accompanied by higher mortality rates than immunological responders (IRs). This study aimed to discover the genes, which help to distinguish INRs from IRs and explore the possible mechanism of INRs.Methods: Screening DEGs between INRs and IRs using GEO microarray dataset GSE143742. DEG biological functions were investigated using GO and KEGG analysis. DEGs and WGCNA linked modules were intersected to find common genes. Key genes were identified using SVM-RFE and LASSO regression models. ROC analysis was done to evaluate key gene diagnostic effectiveness using GEO database dataset GSE106792. Cytoscape created a miRNA-mRNA-TF network for diagnostic genes. CIBERSORT and flow cytometry examined the INRs and IRs immune microenvironments. In 10 INR and 10 IR clinical samples, diagnostic gene expression was verified by RT-qPCR and Western blot.Results: We obtained 190 DEGs between the INR group and IR group. Functional enrichment analysis found a significant enrichment in mitochondria and apoptosis-related pathways. CD69 and ZNF207 were identified as pote

Fengjuan Zhang,1 Chao Yang,1 Zhiyuan Xing,2 Pei Liu,1 Bo Zhang,3 Xiang Ma,4 Liuye Huang,3 Likun Zhuang51Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 3Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, People’s Republic of China; 4Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 5Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of ChinaBackground: MiR-1323 was identified in 2006. Until now, the roles and mechanisms of miR-1323 in the progression of cancers including hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to investigate the expressions, roles and mechanisms of miR-1323 in HCC development.Methods: QRT-PCR was used to evaluate the expressions of miR-1323, GAS5 and TP53INP1 in HCC tissues and cell lines. CCK-8 assay, transwell invasion assay and flow cytometry assay were conducted to evaluate the proliferation, invasion and apoptosis of HCC cells. Luciferase assay was used to identify microRNA-target interaction.Results: Firstly, our results showed that miR-1323 promoted proliferation and invasion, and inhibited apoptosis of HCC cells. Secondly, we found that TP53INP1 was a direct target of miR-1323 and could reverse the effects of miR-1323 on proliferation, invasion and apoptosis of HCC cells. Thirdly, our results showed that long non-coding RNA (lncRNA) GAS5 and miR-1323 could interact with each other and affect biological processes of HCC cells. Furthermore, we identified the negative correlations between miR-1323 and TP53INP1, and between miR-1323 and GAS5

Wenbo Shao, Fengjuan Zhang, Ning Cong, Jinpeng Li, Jinlong SongDepartment of Surgical Oncology (Interventional Therapy), Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People’s Republic of ChinaObjective: To investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in Chinese hepatocellular carcinoma (HCC) patients with low serum HBV DNA level, and to analyze the factors related to HBV reactivation in HCC patients with low serum HBV DNA level.Methods: From November 2011 to January 2014, 109 patients newly diagnosed with HCC with an HBV DNA level less than 2,000 IU/mL were enrolled in the study. These patients underwent at least two TACE procedures and were followed-up for at least 3 months to assess the reactivation of HBV DNA. Ten variables were compared in patients with and without HBV reactivation to evaluate the factors related to HBV reactivation in HCC patients with low serum HBV DNA level.Results: Of 109 HCC patients with low level HBV DNA, nine patients were HBeAg-positive, the other 100 patients were HBeAg-negative. Twenty-three of 109 (21.1%) patients developed HBV reactivation after TACE. Of nine HBeAg-positive patients, 55.6% (5/9) developed HBV reactivation, while in 100 HBeAg-negative patients, the rate of HBV reactivation was 18% (18/100) (P=0.019). Of ten variables of patients with low level HBV DNA, the levels of AFP and HBeAg status were found to be significantly correlated with HBV reactivation. Nevertheless, on binary logistic regression analysis, only HBeAg-positive status was the independent predictor of HBV reactivation in HCC patients with low serum HBV DNA level (odds ratio, 7.41; P=0.013).Conclusion: HCC patients with low serum HBV DNA level still remain associated with risk of viral reactivation after TACE, and HBeAg-positive HCC patients have a higher risk than patients with HBeAg-negative status.Keywords: HBV DNA, viral re