title: Punctuated chromatin states regulate Plasmodium falciparum antigenic variation at the intron and 2 kb upstream regions.
abstract: Understanding 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.
  
  
  
  We 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.
  
  
  
  By 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.
authors.affiliation: Department of Global Health (GH) & Center for Drug Discovery and Innovation (CDDI), College of Public Health, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Chengqi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Global Health (GH) & Center for Drug Discovery and Innovation (CDDI), College of Public Health, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Swamy R
authors.initials: SR
authors.lastname: Adapa
authors.affiliation: Department of Global Health (GH) & Center for Drug Discovery and Innovation (CDDI), College of Public Health, University of South Florida, Tampa, FL, 33612, USA.|Department of Molecular Medicine, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Gibbons
authors.affiliation: Department of Global Health (GH) & Center for Drug Discovery and Innovation (CDDI), College of Public Health, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sutton
authors.affiliation: Department of Global Health (GH) & Center for Drug Discovery and Innovation (CDDI), College of Public Health, University of South Florida, Tampa, FL, 33612, USA. Jiang2@health.usf.edu.
authors.forename: Rays H Y
authors.initials: RH
authors.lastname: Jiang
mesh_terms: D001482:Base Composition; D002843:Chromatin / Q000235:genetics*; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D018503:Genome, Protozoan; D007438:Introns; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics*
chemical_list: D002843:Chromatin; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
keywords: 2 kb upstream region; Chromatin accessibility; FAIRE-Seq; Intron; MNase-Seq; Var gene