Hepatitis B Virus X Protein-Induced Aberrant Epigenetic Modifications Contributing to Human Hepatocellular Carcinoma Pathogenesis

Hepatocellular carcinoma (HCC) remains one of the most prevalent malignant diseases worldwide, and the majority of cases are related to hepatitis B virus (HBV) infection. Interactions between the HBV-encoded X (HBx) protein and host factors are known to play major roles in the onset and progression of HBV-related HCC. These dynamic molecular mechanisms are extremely complex and lead to prominent changes in the host genetic and epigenetic architecture. This review summarizes the current knowledge about HBx-induced epigenetic changes, including aberrations in DNA methylation, histone modifications, and microRNA expression, and their roles in HBV-infected liver cells and HBV-related HCC. Moreover, the HBx-mediated epigenetic control of HBV covalently closed circular DNA (cccDNA) is also discussed. Although this field of study is relatively new, the accumulated evidence has indicated that the epigenetic events induced by HBx play important roles in the development of HBV-related HCC. Ongoing research will help to identify practical applications of the HBV-related epigenetic signatures as biomarkers for early HCC detection or as potential targets to prevent and treat HBV-related HCC.     

Lysine methylation: beyond histones

Posttranslational modifications (PTMs) of histone proteins, such as acetylation, methylation, phosphorylation, and ubiquitylation, play essential roles in regulating chromatin dynamics. Combinations of different modifications on the histone proteins, termed 'histone code' in many cases, extend the information potential of the genetic code by regulating DNA at the epigenetic level. Many PTMs occur on non-histone proteins as well as histones, regulating protein-protein interactions, stability, localization, and/or enzymatic activities of proteins involved in diverse cellular processes. Although protein phosphorylation, ubiquitylation, and acetylation have been extensively studied, only a few proteins other than histones have been reported that can be modified by lysine methylation. This review summarizes the current progress on lysine methylation of non-histone proteins, and we propose that lysine methylation, like phosphorylation and acetylation, is a common PTM that regulates proteins in diverse cellular processes.     

Chromosome remodeling related to hepatitis B virus replication in HepG2 cells

Hepatitis B Virus (HBV) covalently closed circular DNA (cccDNA) is the main replicative intermediate of HBV and is organized into minichromosomes by the interaction with histone and nonhistone proteins. The remodeling of HBV minichromosomes such as post-translational modifications of histone proteins plays an important role in regulating HBV replication. To determine whether other remodeling occurs in addition to acetylation of cccDNA-bound H3 histones in the presence of HBV replication, a cell culture replication model of HBV was used to assess the dynamic status of acetylation, phosphorylation, and methylation of cccDNA-bound H3 histones at various times after transient transfection of linear HBV DNA into human hepatoma, HepG2 cells. H3 histones bound to cccDNA were found to be phosphorylated, mono-methylated, and acetylated in HepG2 cells containing replicating HBV. The acetylation and methylation status of H3 histones bound to cccDNA paralleled HBV replication. Our results demonstrate that phosphorylation and methylation occur in the remodeling of HBV minichromosomes during HBV replication. The modifications of cccDNA-bound H3 histones were associated with the level of HBV replication. These findings suggest that alterations in the extent of minichromosome remodeling might be a potential target to inhibit HBV replication in the development of effective novel antiviral agents.     

乙型肝炎病毒共价键闭环DNA的表观遗传调控研究进展

乙型肝炎病毒(hepatitis B virus,HBV)感染仍然是威胁全球人类生命与健康的重要危险因素。虽然目前的抗病毒治疗药物在控制乙型肝炎进展有显著疗效,但却始终无法达到根治HBV感染的目标。HBV共价闭合环状DNA(HBV cccDNA)是HBV转录复制的原始模板,也是HBV持续感染的关键因素。但由于缺少有效的完全清除HBV cccDNA的治疗方法,慢性乙型肝炎患者需长期服药以防治疗后停药复发。研究证实HBV cccDNA的转录受表观遗传机制调控,其中cccDNA甲基化、组蛋白修饰、miRNA、染色质重塑等均影响HBV cccDNA的功能。本文就HBV表观遗传调控的最新研究进展进行综述。     

Post-translational modifications drive secondary metabolite biosynthesis in Aspergillus: a review

Post-translational modifications (PTMs) are important for protein function and regulate multiple cellular processes and secondary metabolites (SMs) in fungi. Aspergillus species belong to a genus renown for an abundance of bioactive secondary metabolites, many important as toxins, pharmaceuticals and in industrial production. The genes required for secondary metabolites are typically co-localized in biosynthetic gene clusters (BGCs), which often localize in heterochromatic regions of genome and are ‘turned off’ under laboratory condition. Efforts have been made to ‘turn on’ these BGCs by genetic manipulation of histone modifications, which could convert the heterochromatic structure to euchromatin. Additionally, non-histone PTMs also play critical roles in the regulation of secondary metabolism. In this review, we collate the known roles of epigenetic and PTMs on Aspergillus SM production. We also summarize the proteomics approaches and bioinformatics tools for PTM identification and prediction and provide future perspectives on the emerging roles of PTM on regulation of SM biosynthesis in Aspergillus and other fungi.