Abstract
BackgroundUnderstanding the regulation mechanism of var gene expression is crucial for explaining antigenic variation in Plasmodium falciparum. Recent work observed that while all var genes produce transcripts, only a few var genes exhibit high expression levels. However, the global regulation of var expression and the relationship between epigenetic and genetic control remains to be established.ResultWe have systematically reanalyzed the existing genomic data including chromatin configurations and gene expressions; and for the first time used robust statistical methods to show that the intron and 2 kb upstream regions of each endogenous var gene always maintain high chromatin accessibility, with high potential to bind transcription factors (TFs). The levels of transcripts for different var gene family members are associated with this chromatin accessibility. Any given var gene thus shows punctuated chromatin states throughout the asexual life cycle. This is demonstrated by three independent transcript datasets. Chromatin accessibility in the var intron and 2 kb upstream regions are also positively correlated with their GC content, suggesting the level of var genes silencing might be encoded in their intron sequences. Interestingly, both var intron and 2 kb upstream regions exhibit higher chromatin accessibility when the genes have relatively lower transcription levels, suggesting a punctuated repressive function for these regulatory elements.ConclusionBy integrating and analyzing epigenomic, genomic and transcriptomic data, our work reveals a novel distal element in var control. We found dynamic modulations of specific epigenetic marks around the var intron and distal upstream regions are involved in the general var gene expression patterns in malarial antigenic variation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3005-7) contains supplementary material, which is available to authorized users.
Highlights
Understanding the regulation mechanism of var gene expression is crucial for explaining antigenic variation in Plasmodium falciparum
Genome wide intron scan reveals all var gene introns maintain high chromatin accessibility Earlier transgenic works showed that the var intron is required for var gene silencing [12, 29]
By using FAIRE-Seq and MNase-Seq data, we first showed that relatively lower chromatin accessibility in both the intron and 2 kb upstream regions is associated with higher var gene expression
Summary
Understanding the regulation mechanism of var gene expression is crucial for explaining antigenic variation in Plasmodium falciparum. The most prominent virulent surface antigen in P. falcuparum is the protein PfEMP1 (P. falciparum erythrocytic membrane protein 1) encoded by the var multi-copy gene family [2,3,4,5]. Research over the past 10 years has identified var intron and promoter elements as key for var gene silencing. Et al first observed that a luciferase gene can be silenced by placing a var intron at the gene’s 3′ end [8]. Using transfected plasmids Voss et al found that a var gene upstream region is capable of silencing a gene thereby promoting mono-allelic expression [9].
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