PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum.

Lubin Jiang (1) , Jianbing Mu (2) , Qingfeng Zhang (3, 4) , Ting Ni (5) , Prakash Srinivasan (2) , Kempaiah Rayavara (2) , Wenjing Yang (6) , Louise Turner (7) , Thomas Lavstsen (7) , Thor G Theander (7) , Weiqun Peng (8) , Guiying Wei (3) , Qingqing Jing (1) , Yoshiyuki Wakabayashi (6) , Abhisheka Bansal (2) , Yan Luo (6) , José M C Ribeiro (2) , Artur Scherf (4) , L. Aravind (9) , Jun Zhu (6) , Keji Zhao (10) , Louis H Miller (2)

1 LMVI - Key Laboratory of Molecular Virology & Immunology
2 Laboratory of Malaria and Vector Research
3 Institute of Infectious Diseases and Vaccine Development
4 Biologie des Interactions Hôte-Parasite
5 State Key Laboratory of Genetics Engineering & MOE Key Laboratory of Contemporary Anthropology
6 Genetics and Development Biology Center
7 Centre for Medical Parasitology [Copenhagen]
8 Department of Physics
9 NCBI - National Center for Biotechnology Information
10 Systems Biology Center

The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.

Domaines: Sciences du Vivant [q-bio]

Lubin Jiang, Jianbing Mu, Qingfeng Zhang, Ting Ni, Prakash Srinivasan, et al.. PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum.. Nature, 2013, epub ahead of print. ⟨10.1038/nature12361⟩. ⟨pasteur-00842612⟩