title: The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state.
abstract: With about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1). Consistently, inhibiting or reducing LSD1 levels led to repression of viral gene expression. This correlates with the transcriptionally repressive mark H3K9 methylation and reduction on the activating marks H3 acetylation and H3K4 methylation on viral promoters. Investigating the importance of viral proteins we found that LSD1 recruitment to viral promoters was dependent on the viral transactivator protein HBx. Moreover, the histone methyltransferase Set1A and HBx are simultaneously bound to the core promoter, and Set1A expression correlates with cccDNA H3K4 methylation. Our results shed light on the mechanisms of HBV regulation mediated by the cccDNA chromatin structure, offering new therapeutic targets to develop drugs for the treatment of chronically infected HBV patients.
authors.affiliation: Fundación Ciencia &Vida, 7780272, Santiago, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: Alarcon
authors.affiliation: Laboratorio de Virus Hepatitis, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hernández
authors.affiliation: Fundación Ciencia &Vida, 7780272, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rubio
authors.affiliation: Fundación Ciencia &Vida, 7780272, Santiago, Chile.
authors.forename: Francisca
authors.initials: F
authors.lastname: Alvarez
authors.affiliation: Fundación Ciencia &Vida, 7780272, Santiago, Chile.
authors.forename: Yvo
authors.initials: Y
authors.lastname: Flores
authors.affiliation: Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Varas-Godoy
authors.affiliation: Centro de Investigaciones Biomédicas. Facultad de Ciencias Biológicas y Facultad de Medicina. Universidad Andres Bello, Santiago, Chile.
authors.forename: Giancarlo V
authors.initials: GV
authors.lastname: De Ferrari
authors.affiliation: Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.|CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.|CHU de Bordeaux, Bordeaux, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Kann
authors.affiliation: Laboratorio de Virus Hepatitis, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Villanueva
authors.affiliation: Fundación Ciencia &Vida, 7780272, Santiago, Chile.|Universidad San Sebastián, Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Loyola
mesh_terms: D000107:Acetylation; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000378:metabolism* / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D056466:Histone Demethylases / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
chemical_list: D002843:Chromatin; D006657:Histones; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D056466:Histone Demethylases; C495195:KDM1A protein, human; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human