Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Global prophylactic vaccination programmes have helped to curb new hepatitis B virus(HBV)infections.However,it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma.As such,HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed.Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA(cccDNA)which establishes itself as a minichromosome in the nucleus of hepatocytes.As the viral transcription intermediate,the cccDNA is responsible for producing new virions and perpetuating infection.HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications.Two HBV proteins,X(HBx)and core(HBc)promote viral replication by modulating the cccDNA epigenome and regulating host cell responses.This includes viral and host gene expression,chromatin remodeling,DNA methylation,the antiviral immune response,apoptosis,and ubiquitination.Elimination of the cccDNA minichromosome would result in a sterilizing cure;however,this may be difficult to achieve.Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure.This review explores the cccDNA epigenome,how host and viral factors influence transcription,and the recent epigenetic therapies and epigenome engineering approaches that have been described.

Epigenetic regulation mechanism of ABCG2 induced drug-resistant phenotype

The aim of this study is to investigate epigenetic mechanism of ABCG2 induced drug-resistance. It is not only expatiate for drug-resistance regulation mechanism in all-round, but also to provide scientific experimental basis for selecting target to reverse its drug-resistance. Apply methylation-specific PCR （MSP） to have tested methylation of ABCG2 promoter region -359 to -353 specific positions in breast cancer tissues and paired adjacent tissue of 22 cases and test their methylation positions with MSP products for sequencing; and adopt fluorescent quantitation RT-PCR to test expression level DNMT1, DNMT3A, DNMT3B and ABCG2; to make analysis on relationship between them with statistical spearman correlation. Specific positions of ABCG2 gene promoter region of 18 cases among the 22 cases with breast cancer （18/22, 82%） existed high methylation （P〈0.05）, MSP products sequencing proved methylation of the specific position, and mRNA expression level was relative higher in remarkable positive correlation （P〈0.05） ABCG2, DNMT1, DNMT3A, DNMT3B mRNA expression levels in breast cancer tissues were obviously higher than adjacent tissues （P〈0.01）, and DNMT3B expression level was obviously higher than DNMT1 and DNMT3A （P〈0.01） in negative correlation with ABCG2 gene expression （P=0.001）. -359 to -353 positions of promoter regions of ABCG2gene existed high methylation capable to push expression of this gene in beast cancer tissue. DNMT3B is involved in expression regulation in ABCG2 gene, and provides new scientific basis for drug-resistance target as reverse ABCG2 induction

Current understanding of adenoid cystic carcinoma in the gene expression and targeted therapy

Adenoid Cystic Carcinoma(ACC)has been considered as a"quiet"tumor.It is typically malignancy arising from exocrine glands with poor long-term prognosis due to high rate of recurrence and distant metastasis.It is characterized by perineural infiltration,distant metastasis,and positive incision edge.Surgery is the first line treatment for ACC,followed by cytotoxic chemotherapy and/or radiotherapy as adjuvant treatments to avoid recurrence.But recurrence or metastasis still occurs in more than 50%ACC.Recurrent and/or metastasis(R/M)ACC is usually incurable,and no systemic agent has been found effective.With the widespread use of whole exome sequencing(WES)and whole genome sequencing(WGS),its internal oncogenic mechanism is gradually revealed,which involving molecular mutations such as the MYB family gene translocation,Notch signal pathway,DNA damage repair(DDR)pathway and epigenetic molecular mutations.The review helps us to understand the linkage among the pathways and targeted genes in diagnosis and related treatment of ACC till now.

Antagonism between gene therapy and epigenetic therapy on human laryngeal carcinoma tumor-bearing mice

Background Gene therapy and epigenetic therapy have gained more attention in cancer treatment. However, the effect of a combined treatment of gene therapy and epigenetic therapy on head and neck squamous cell carcinoma have not been studied yet. To study the mechanism and clinical application, human laryngeal carcinoma cell （Hep-2） tumor-bearing mice were used. Methods A xenograft tumor model was established by the subcutaneous inoculation of Hep-2 cells in the right armpit of BALB/c nu/nu mice. The mice with well-formed tumor were randomly divided into six groups. Multisite injections of rAd-p53 and/or 5-aza-dC were used to treat tumor. Tumor growth was monitored by measuring tumor volume and growth rate. p53 and E-cadherin protein levels in tumor tissues were detected by immunohistochemical staining. The mRNA levels were monitored with FQ-PCR. Results Gene therapy was much more effective than single epigenetic therapy and combined therapy. The gene therapy group has the lowest tumor growth rate and the highest expression levels of p53 and E-cadherin. Conclusions The combined treatment of gene and epigenetic therapy is not suggested for treating head and neck carcinoma, because gene therapy shows an antagonistic effect to epigenetic therapy. However, the mechanisms of action are still unclear.

XAANTAL2 （AGL14） Is an Important Component of the Complex Gene Regulatory Network that Underlies Arabidopsis Shoot Apical Meristem Transitions

In Arabidopsis thaliana, multiple genes involved in shoot apical meristem （SAM） transitions have been char- acterized, but the mechanisms required for the dynamic attainment of vegetative, inflorescence, and floral meristem （VM, IM, FM） cell fates during SAM transitions are not well understood. Here we show that a MADS-box gene, XAANTAL2 （XAL2/AGL14）, is necessary and sufficient to induce flowering, and its regula- tion is important in FM maintenance and determinacy, xal2 mutants are late flowering, particularly under short-day （SD） condition, while XAL2 overexpressing plants are early flowering, but their flowers have vege- tative traits. Interestingly, inflorescences of the latter plants have higher expression levels of LFY, AP1, and TFL1 than wild-type plants. In addition we found that XAL2 is able to bind the TFL1 regulatory regions. On the other hand, the basipetal carpels of the 35S：：XAL2 lines lose determinacy and maintain high levels of WUS expression under SD condition. To provide a mechanistic explanation for the complex roles of XAL2 in SAM transitions and the apparently paradoxical phenotypes of XAL2 and other MADS-box （SOCl, AGL24） over- expressors, we conducted dynamic gene regulatory network （GRN） and epigenetic landscape modeling. We uncovered a GRN module that underlies VM, IM, and FM gene configurations and transition patterns in wild- type plants as well as loss and gain of function lines characterized here and previously. Our approach thus provides a novel mechanistic framework for understanding the complex basis of SAM development.