Deciphering transcriptional regulatory elements that encode specific cell cycle phasing by comparative genomics analysis

Transcriptional regulation is a major tier in the periodic engine that mobilizes cell cycle progression. The availability of complete genome sequences of multiple organisms holds promise for significantly improving the specificity of computational identification of functional elements. Here, we applied a comparative genomics analysis to decipher transcriptional regulatory elements that control cell cycle phasing. We analyzed genome-wide promoter sequences from 12 organisms, including worm, fly, fish, rodents and human, and identified conserved transcriptional modules that determine the expression of genes in specific cell cycle phases. We demonstrate that a canonical E2F signal encodes for expression highly specific to the G₁/S phase, and that a cis-regulatory module comprising CHR-NF-Y elements dictates expression that is restricted to the G₂ and G₂/M phases. B-Myb binding site signatures occur in many of the CHR-NF-Y target genes, suggesting a specific role for this triplet in the regulation of the cell cycle transcriptional program. Remarkably, E2F signals are conserved in promoters of G₁/S genes in all organisms from worm to human. The CHR-NF-Y module is conserved in promoters of G₂/M regulated genes in all analyzed vertebrates. Our results reveal novel modules that determine specific cell cycle phasing, and identify their respective putative target genes with remarkably high specificity.