The HBV cccDNA has been shown to be organized in a chromatin like structure associated with histone and none histone proteins including the viral core protein however its role on cccDNA regulation is poorly understood. The synthesis of viral transcripts is controlled by four promoters and two enhancers , which are regulated by various transcription factors and coactivators. Moreover like cellular chromatin, HBV transcription is regulated through chromatin organization and modulation of epigenetic marks on DNA and histones.
Beside cellular factors, the regulatory protein HBx has been shown to be essential for viral replication in vivo. While HBx might participate in the viral life cycle via different mechanisms, it is believed to primary act at the level of transcription. The role of HBx on HBV transcription is still poorly understood and HBx might act through interactions with transcriptional regulators. We identified mechanisms by which HBx activates cccDNA transcription through the inhibition of cellular factors involved in transcriptional and chromatin regulation, such as the PP1/HDAC1 complex and PRMT1 (Cougot et al., Sci Signal., 2012; Benhenda et al., J. Virol., 2013). Thanks to the development of a tissue culture infection model, we were recently able to assess cccDNA transcriptional regulation in the setting of infection. We showed that HBx is needed to counteract the transcriptional silencing of the cccDNA that is mediated by the establishment of repressed chromatin associated with H3K9me3 and HP1 recruitment. We demonstrated that SETDB1 is the main histone methyltransferase responsible for the establishment of repressed chromatin (Riviere et al., J Hepatol. 2015).
To gain insight into cccDNA biology we are studying the chromatin structure of the cccDNA and the role of cellular and viral proteins in HBV cccDNA chromatin regulation.