Cell cycle-regulated transcription: effectively using a genomics toolbox

Abstract

The cell cycle comprises a series of temporally ordered events that occur sequentially, including DNA replication, centrosome duplication, mitosis, and cytokinesis. What are the regulatory mechanisms that ensure proper timing and coordination of events during the cell cycle? Biochemical and genetic screens have identified a number of cell-cycle regulators, and it was recognized early on that many of the genes encoding cell-cycle regulators, including cyclins, were transcribed only in distinct phases of the cell cycle. Thus, "just in time" expression is likely an important part of the mechanism that maintains the proper temporal order of cell cycle events. New high-throughput technologies for measuring transcript levels have revealed that a large percentage of the Saccharomyces cerevisiae transcriptome (~20 %) is cell cycle regulated. Similarly, a substantial fraction of the mammalian transcriptome is cell cycle-regulated. Over the past 25 years, many studies have been undertaken to determine how gene expression is regulated during the cell cycle. In this review, we discuss contemporary models for the control of cell cycle-regulated transcription, and how this transcription program is coordinated with other cell cycle events in S. cerevisiae. In addition, we address the genomic approaches and analytical methods that enabled contemporary models of cell cycle transcription. Finally, we address current and future technologies that will aid in further understanding the role of periodic transcription during cell cycle progression.

Fig. 1

Cell-cycle progression in Saccharomyces cerevisiae. Budding yeast serves as an excellent model system to study the cell cycle. Timing and regulation of events are conserved across species. More importantly, the phase of the cell cycle can be deduced by observing the state and size of the bud, the future daughter cell

Fig. 2

Significance of the periodic transcription program. (a) Genes are expressed only during the cell-cycle phase needed. Genes required for DNA replication are expressed during S phase. (b) The temporal order of gene expression may aid in the construction of a protein complex only needed once per cycle. (c) While protein levels of cell-cycle regulators may remain constant, posttranslational modifications may alter the activity of the proteins

Fig. 3

Cell-cycle transcription network. An interconnected network of transcription factors that demonstrate how a transcriptional signal could be passed through the cell cycle. Note that this is just one representation of a TF network. Based on significance cutoffs and TFs included, different networks may be constructed. Boxes are nodes. Green, transcriptional activators; red, transcriptional repressors; blue, posttranslational modifications. Arrows signify either an upstream promoter binding to the promoter of the downstream target (black arrows) or a posttranslational modification that affects the activity of the TF (blue arrows). Nodes are placed on a cell-cycle timeline based on time of peak expression in wild-type cells (Color figure online)

Fig. 4

Model of cell-cycle regulation. A transcription factor network is responsible for regulating the timing of the periodic transcriptional program, including cyclins. Cyclins, in complex with CDKs, then act as effectors to trigger events at the proper time after periodic synthesis

Fig. 5

Logics of multiple transcription factors regulating a single target affect its synthesis. Depending on the combinations of transcription factors that bind to the promoter of a single target, they may work together (AND logic) or may work separately (OR logic). Repressors most likely override any activators that may be bound at the same time (AND NOT logic). Depending on the number and combination of potential regulators, other logics may be possible