title: Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1.
abstract: BACKGROUND
  The acquisition of multidrug resistance by Plasmodium falciparum underscores the need to understand the underlying molecular mechanisms so as to counter their impact on malaria control. For the many antimalarials whose mode of action relates to inhibition of heme detoxification inside infected erythrocytes, the digestive vacuole transporters PfCRT and PfMDR1 constitute primary resistance determinants.
  
  
  RESULTS
  Using gene expression microarrays over the course of the parasite intra-erythrocytic developmental cycle, we compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels. To account for differences in the time of sampling, we developed a computational method termed Hypergeometric Analysis of Time Series, which combines Fast Fourier Transform with a modified Gene Set Enrichment Analysis. Our analysis revealed coordinated changes in genes involved in protein catabolism, translation initiation and DNA/RNA metabolism. We also observed differential expression of genes with a role in transport or coding for components of the digestive vacuole. Interestingly, a global comparison of all profiled transcriptomes uncovered a tight correlation between the transcript levels of pfcrt and pfmdr1, extending to dozens of other genes, suggesting an intricate regulatory balance in order to maintain optimal physiological processes.
  
  
  CONCLUSIONS
  This study provides insight into the mechanisms by which P. falciparum adjusts to the acquisition of mutations or gene amplification in key transporter loci that mediate drug resistance. Our results implicate several biological pathways that may be differentially regulated to compensate for impaired transporter function and alterations in parasite vacuole physiology.
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, 10032, USA. sa18@sanger.ac.uk.|Present addresses: Wellcome Trust Sanger Institute, Hinxton, UK. sa18@sanger.ac.uk.
authors.forename: Sophie H
authors.initials: SH
authors.lastname: Adjalley
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, 10032, USA. scanfeld@gmail.com.|Present addresses: Google Inc., New York, NY, 10011, USA. scanfeld@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scanfeld
authors.affiliation: Department of Molecular Biology & Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA. elyseko@bu.edu.|Present addresses: Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA. elyseko@bu.edu.
authors.forename: Elyse
authors.initials: E
authors.lastname: Kozlowski
authors.affiliation: Department of Molecular Biology & Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA. manuel@psu.edu.|Department of Biochemistry and Molecular Biology, Department of Chemistry, Center for Malaria Research and Center for Infectious Diseases Dynamics, Pennsylvania State University, University Park, PA, 16802, USA. manuel@psu.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llinás
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, 10032, USA. df2260@columbia.edu.|Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA. df2260@columbia.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D019295:Computational Biology / Q000379:methods; D018432:Drug Resistance, Multiple; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D026901:Membrane Transport Proteins / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D010963:Plasmodium falciparum / Q000235:genetics* / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics*
chemical_list: D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum