Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation

PLoS Pathogens

Klaus H. Kaestner¹  Saira Iram²  Rasha E. Shalaby²  Alan McLachlan²  Vanessa C. McFadden²  Claudia E. Oropeza²  Mark Maienschein-Cline³  Stefan J. Green³  Alexander V. Lyubimov⁴  Jennifer A. Landolfi⁴ 

[1] Department of Genetics University of Pennsylvania School of Medicine Philadelphia, PA, United States of America;Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago 909 South Wolcott Avenue Chicago, IL, United States of America;Research Resources Center College of Medicine University of Illinois at Chicago 835 South Wolcott Avenue Chicago, IL, United States of America;Toxicology Research Laboratory Department of Pharmacology College of Medicine University of Illinois at Chicago Chicago, IL, United States of America

关键词: DNA methylation;    Mouse models;    DNA transcription;    Mammalian genomics;    Transcription factors;    Gene expression;    Hepatocytes;    DNA replication;   

DOI  :  10.1371/journal.ppat.1006239

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The FoxA family of pioneer transcription factors regulates hepatitis B virus (HBV) transcription, and hence viral replication. Hepatocyte-specific FoxA-deficiency in the HBV transgenic mouse model of chronic infection prevents the transcription of the viral DNA genome as a result of the failure of the developmentally controlled conversion of 5-methylcytosine residues to cytosine during postnatal hepatic maturation. These observations suggest that pioneer transcription factors such as FoxA, which mark genes for expression at subsequent developmental steps in the cellular differentiation program, mediate their effects by reversing the DNA methylation status of their target genes to permit their ensuing expression when the appropriate tissue-specific transcription factor combinations arise during development. Furthermore, as the FoxA-deficient HBV transgenic mice are viable, the specific developmental timing, abundance and isoform type of pioneer factor expression must permit all essential liver gene expression to occur at a level sufficient to support adequate liver function. This implies that pioneer transcription factors can recognize and mark their target genes in distinct developmental manners dependent upon, at least in part, the concentration and affinity of FoxA for its binding sites within enhancer and promoter regulatory sequence elements. This selective marking of cellular genes for expression by the FoxA pioneer factor compared to HBV may offer the opportunity for the specific silencing of HBV gene expression and hence the resolution of chronic HBV infections which are responsible for approximately one million deaths worldwide annually due to liver cirrhosis and hepatocellular carcinoma.

【 授权许可】

CC BY