Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency

Yu Liang, Jodi L. Vogel, Jesse H. Arbuckle, Ganesha Rai, Ajit Jadhav, Anton Simeonov, David J. Maloney, Thomas M. Kristie1. Sci. Transl. Med, 2013. 5, 167ra5

Speaker: Yu-Rou Liao (廖毓柔)                                     Time: 14:00~15:00, Nov.27, 2013

Commentator: Dr. Guey-Chuen Perng (彭貴春 老師)  Place: Room 601

Abstract:

Although the advancement in the treatment of herpesvirus-associated diseases has developed some antiherpetic drugs, these drugs that target the late stage of viral infection are not completely effective in preventing recurrent reactivation, avoiding immune-mediated damages and capturing resistant viral mutants. Here, the authors explored the molecules in epigenetic regulation that is essential for DNA viruses to initiate gene expression during infection or reactivation. Nucleosomes are assembled on the viral gene promoters bearing repressive histone H3-Lys9 methylation in the beginning of infection and reactivation [1]. On this basis, DNA viruses require cellular and viral transcriptional components to remove the repressive marks and turn into activating marks for successful infection. Therefore, targeting histone demethylases is potential to control viral infection at an early stage [2]. The authors revealed that JMJD2 H3K9 demethylase family members synergistically activate immediate early (IE) gene expression of herpes simplex virus 1. Additionally, similar results were also observed on the IE gene expression of β-herpesvirus human cytomegalovirus. According to these findings, a new epigenetic-based inhibitor was developed to suppress the activity of JMJD2 demethylases. This new inhibitor, ML34, potently prevents the infection of α-herpesvirus or β-herpesvirus and blocks the reactivation of herpes simplex virus 1 from latency. Notably, this approach provides a new direction to develop antiviral therapies for treatment of DNA virus infection via targeting the initial activities on viral IE promoters that might break the limitations of present available drugs.

References:

1.     Silva, L., et al., Role for A-type lamins in herpesviral DNA targeting and heterochromatin modulation. PLoS Pathog, 2008. 4(5): p. e1000071.

2.     Liang, Y., et al., Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med, 2009. 15(11): p. 1312-7.