Genome wide distribution of G-quadruplexes and their impact on gene expression in malaria parasites

Abstract

Mechanisms of transcriptional control in malaria parasites are still not fully understood. The positioning patterns of G-quadruplex (G4) DNA motifs in the parasite's AT-rich genome, especially within the var gene family which encodes virulence factors, and in the vicinity of recombination hotspots, points towards a possible regulatory role of G4 in gene expression and genome stability. Here, we carried out the most comprehensive genome-wide survey, to date, of G4s in the Plasmodium falciparum genome using G4Hunter, which identifies G4 forming sequences (G4FS) considering their G-richness and G-skewness. We show an enrichment of G4FS in nucleosome-depleted regions and in the first exon of var genes, a pattern that is conserved within the closely related Laverania Plasmodium parasites. Under G4-stabilizing conditions, i.e., following treatment with pyridostatin (a high affinity G4 ligand), we show that a bona fide G4 found in the non-coding strand of var promoters modulates reporter gene expression. Furthermore, transcriptional profiling of pyridostatin-treated parasites, shows large scale perturbations, with deregulation affecting for instance the ApiAP2 family of transcription factors and genes involved in ribosome biogenesis. Overall, our study highlights G4s as important DNA secondary structures with a role in Plasmodium gene expression regulation, sub-telomeric recombination and var gene biology.

G-quadruplexes in H1N1 influenza genomes

“…There are accessible several tools to analyze PQS in genomic sequences (reviewed in [16]). We used the G4Hunter algorithm where G4 propensity is calculated depending on G richness and G/C skewness and PQS are evaluated quantitatively [17] and validated experimentally [17,18]. We used a new G4Hunter algorithm implementation, which is suitable for batch and full genomes analyses [19,20] and accessible as the web-tool G4Hunter web [21].…”

G-Quadruplexes in the Archaea Domain

“…In both bacteria and eukaryotes, G4 formation regulates various processes, including gene expression [ 22 ], protein translation [ 23 ], and proteolysis [ 24 ]. G4 have been identified in a number of pathogens, including viruses, eukaryotes (e.g., Plasmodium falciparum ) [ 25 , 26 ] or prokaryotes (e.g., Neissseria gonorrhoeae [ 27 ], and Mycobacterium tuberculosis ) [ 28 , 29 ]. Moreover, many G4-binding proteins are conserved in all organisms highlighting the importance of the G4 structure regulations [ 30 ], and novel G4 binding proteins have been identified, sharing the NIQI amino acid motif (RGRGRRGGGSGGSGGRGRG) [ 31 ].…”

Evaluating the Influence of a G-Quadruplex Prone Sequence on the Transactivation Potential by Wild-Type and/or Mutant P53 Family Proteins through a Yeast-Based Functional Assay

“…Interestingly, G4s are often located in promoter sequences as shown for many human genes [ 69 , 70 , 71 ], including P53 targets; in fact, the presence of G4 prone sequences has been found around P53 RE in the promoter of the P53-induced apoptotic PUMA protein [ 34 ]. Therefore, the presence and the formation of a G4 structure could be an important transcriptional regulatory element, as previously observed in various organisms including humans [ 72 , 73 , 74 ].…”