Identification of Slug and SOX7 as transcriptional repressors binding to the hepatitis B virus core promoter

Ko, Hui Ling; Lam, Tze Hau; Ng, Huijin; Toh, Jiaying; Wang, Liang Wei; Ren, Ee Chee

doi:10.1016/j.jhep.2017.08.033

Cited by 9 publications

(22 citation statements)

References 36 publications

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“…7). These results indicate a dual role for Sox7 in PGCs as both a negative and positive regulator of transcription, both of which have been previously reported for Sox7 (Charney et al, 2017;Ko et al, 2017;Wang et al, 2014;Futaki et al, 2004;Séguin et al, 2008;Zhang et al, 2005).…”

Section: Pgc Transcriptome Is Conserved Between Xenopus and Human Pgcssupporting

confidence: 84%

A novel role for sox7 in Xenopus early primordial germ cell development: mining the PGC transcriptome

et al. 2018

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primordial germ cells (PGCs) are determined by the presence of maternally derived germ plasm. Germ plasm components both protect PGCs from somatic differentiation and begin a unique gene expression program. Segregation of the germline from the endodermal lineage occurs during gastrulation, and PGCs subsequently initiate zygotic transcription. However, the gene network(s) that operate to both preserve and promote germline differentiation are poorly understood. Here, we utilized RNA-sequencing analysis to comprehensively interrogate PGC and neighboring endoderm cell mRNAs after lineage segregation. We identified 1865 transcripts enriched in PGCs compared with endoderm cells. We next compared the PGC-enriched transcripts with previously identified maternal, vegetally enriched transcripts and found that ∼38% of maternal transcripts were enriched in PGCs, including PGC-directed knockdown and overexpression studies revealed an early requirement for in germ plasm localization, zygotic transcription and PGC number. We identified as the most highly expressed and enriched homolog in PGCs. We compared the PGC transcriptome with human PGC transcripts and showed that 80% of genes are conserved, underscoring the potential usefulness of for understanding human germline specification.

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Section: Pgc Transcriptome Is Conserved Between Xenopus and Human Pgcssupporting

confidence: 84%

A novel role for sox7 in Xenopus early primordial germ cell development: mining the PGC transcriptome

et al. 2018

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“…Our data illustrated that SIRT6 could promote HBV transcription and replication by targeting core promoter. It is well known that efficient transcription of HBV core promoter is essential for 3.5-Kb RNA synthesis and cccDNA accumulation (Ko et al, 2017). Identifying the transcription factors targeting core promoter is critical to elucidate the interaction between SIRT6 and HBV.…”

Section: Discussionmentioning

confidence: 99%

“…It is worth noting that 3.5-Kb RNA not only can work for translation template of secreted e antigen (HBeAg), core protein, and viral polymerase, but also can be packaged into nucleocapsid for reverse transcription. As the promoter of 3.5-Kb RNA, HBV core promoter plays an important role in HBV life cycle and inhibition of core promoter activity can restrict HBV transcription and replication dramatically (Ko et al, 2017). Therefore, transcription silence of HBV core promoter may represent an attractive approach for HBV therapy.…”

Section: Introductionmentioning

confidence: 99%

SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors α

et al. 2019

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Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Toward identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core deoxyribonucleic acid (DNA) and 3.5-Kb ribonucleic acid (RNA) in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-sodium taurocholate cotransporting polypeptide cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.

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“…RNA pull‐down assay was performed as described. ( 21 ) Briefly, pgRNA and its antisense RNA were in vitro transcribed from vector pSPT19‐pgRNA, biotin labeled with the Biotin RNA Labeling Mix (Roche Diagnostics, Indianapolis, IN) and T7/SP6 RNA polymerase (Roche), and purified with an RNeasy Mini Kit (Qiagen, Valencia, CA). One milligram of protein from HepG2.2.15 cells was then mixed with 50 pmol of biotinylated RNA, incubated with streptavidin agarose beads (Invitrogen), and washed.…”

Section: Methodsmentioning

confidence: 99%

HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV‐Related HCC Through Reciprocal Regulation With Insulin‐Like Growth Factor 2 mRNA‐Binding Protein 3

Ding

Wang

et al. 2021

Hepatology

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Background and Aims HBV‐pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV‐pgRNA to HCC remain open for study. Approach and Results Double‐center cohorts of serum samples with undetectable serum HBV‐DNA (below the lower limit of detection) were obtained from long‐term NA‐treated (≥48 weeks) HBV‐related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long‐term NA therapy with undetectable serum HBV‐DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up‐regulate the expression of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), a well‐proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)‐α‐2a could degrade the stability of pgRNA through increasing its N6‐methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long‐term NA therapy with undetectable serum HBV‐DNA; and the pgRNA‐IGF2BP3 axis plays an important role in the development of HBV‐related HCC. Moreover, IFN‐α‐2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV‐related HCC. Conclusions In conclusion, our studies reveal a significance and mechanism of HBV‐pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV‐related HCC.

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Identification of Slug and SOX7 as transcriptional repressors binding to the hepatitis B virus core promoter

Cited by 9 publications

References 36 publications

A novel role for sox7 in Xenopus early primordial germ cell development: mining the PGC transcriptome

A novel role for sox7 in Xenopus early primordial germ cell development: mining the PGC transcriptome

SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors α

HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV‐Related HCC Through Reciprocal Regulation With Insulin‐Like Growth Factor 2 mRNA‐Binding Protein 3

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