UCSF

The mechanisms of gene regulation in the malaria parasite P. falciparum are not well known. However, the genome sequence and existing gene expression datasets are rich resources that can aid in identifying transcriptional regulatory elements. By comparing promoter sequences and expression data in the parasite's intraerythrocytic developmental cycle (IDC) (Bozdech et al. 2003), we computationally identified 11 cis-regulatory sequence motifs whose appearance in promoters correlates with timing of expression. Defining motif activity profile as correlation of motif with expression, each motif has a sinusoidal activity profile with a period equal to that of the IDC. In several cases, the equivalent motif on the reverse strand has an identical activity profile, while other motifs display orientation specific correlations. These motifs occur in the intergenic regions of a large fraction of the genes in the genome, suggesting that they govern a large proportion of the transcriptome. Target gene predictions support this thesis, as a significant fraction of the 3518 genes transcribed periodically during the IDC can be matched to at least one of the 11 motifs. Furthermore, these motifs appear to have strong co-occurrence biases, implying that regulation is frequently combinatorial. One motif was validated by a biochemical approach, and we call this motif the TG box motif. It is predicted to be involved in transcription of 20% of the periodically transcribed genes of the IDC. We have developed a partial purification protocol that yields a candidate polypeptide approximately 12kD in size, which we suggest to be the sequence specific transcription factor with affinity for the TG box motif.