The precise timing of cell cycle gene expression is critical for the control of cell proliferation; de-regulation of this timing promotes the formation of cancer and leads to defects during differentiation and development. Entry into and progression through S phase requires expression of genes coding for proteins that function in DNA replication. Expression of a distinct set of genes is essential to pass through mitosis and cytokinesis. Expression of these groups of cell cycle-dependent genes is regulated by the RB pocket protein family, the E2F transcription factor family, and MuvB complexes together with B-MYB and FOXM1. Distinct combinations of these transcription factors promote the transcription of the two major groups of cell cycle genes that are maximally expressed either in S phase (G1/S) or in mitosis (G2/M). In this review, we discuss recent work that has started to uncover the molecular mechanisms controlling the precisely timed expression of these genes at specific cell cycle phases, as well as the repression of the genes when a cell exits the cell cycle.

bThere are nearly 50 forkhead (FOX) transcription factors encoded in the human genome and, due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here, we used chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G 2 and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR (cell cycle genes homology region) elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor that allows it to specifically control cell cycle-dependent gene expression. There are nearly 50 different forkhead transcription factors encoded in mammalian genomes, and these proteins all contain the conserved forkhead DNA binding domain (reviewed in references 1 and 2). Forkhead transcription factors are involved in controlling a wide range of biological processes and are aberrantly expressed or regulated in disease states, including cancer (reviewed in reference 2). However, due to sharing a common DNA binding domain, forkhead transcription factors are generally believed to bind to variations of the RYAAAYA motif. Hence, it is unclear how individual forkhead proteins are specifically recruited to the regulatory regions of different cohorts of target genes to control defined biological responses. One key process which is controlled by forkhead transcription factors is the cell cycle and, in particular, the G 2 -M transition. The initial links to G 2 -M control were made with the Saccharomyces cerevisiae forkhead protein Fkh2, which controls the temporal expression of a cluster of genes at this phase of the cell cycle (reviewed in reference 3). More recently, members of the FOXO and FOXM classes of forkhead transcription factors have been linked with controlling the same process in mammalian cells (4-6). In both cases, forkhead transcription factors coordinate the integration of signals from the cell cycle regulatory machinery to transcriptional outputs. This is exemplified by the links to the cell cycle regulated Polo-like kinase PLK1, which is recruited to cell cycle-regulated promoters through promoter elements bound by the forkhead transcription factors FOXM1 and Fkh2, albeit indirectly in the case of Fkh2 (7,8).In mammalian cells, the transcriptional control of a cluster of genes at the G 2 -M transition, is coordinated through promoter elements which typically contain CHR (cell cycle genes homology region) and...

Cell cycle-dependent gene expression is often controlled on the transcriptional level. Genes like cyclin B, CDC2 and CDC25C are regulated by cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR) promoter elements mainly through repression in G0/G1. It had been suggested that E2F4 binding to CDE sites is central to transcriptional regulation. However, some promoters are only controlled by a CHR. We identify the DREAM complex binding to the CHR of mouse and human cyclin B2 promoters in G0. Association of DREAM and cell cycle-dependent regulation is abrogated when the CHR is mutated. Although E2f4 is part of the complex, a CDE is not essential but can enhance binding of DREAM. We show that the CHR element is not only necessary for repression of gene transcription in G0/G1, but also for activation in S, G2 and M phases. In proliferating cells, the B-myb-containing MMB complex binds the CHR of both promoters independently of the CDE. Bioinformatic analyses identify many genes which contain conserved CHR elements in promoters binding the DREAM complex. With Ube2c as an example from that screen, we show that inverse CHR sites are functional promoter elements that can bind DREAM and MMB. Our findings indicate that the CHR is central to DREAM/MMB-dependent transcriptional control during the cell cycle.