Timing of transcription during the cell cycle: Protein complexes binding to E2F, E2F/CLE, CDE/CHR, or CHR promoter elements define early and late cell cycle gene expression

Abstract

// Gerd A. Müller 1 , Konstanze Stangner 1 , Thomas Schmitt 1 , Axel Wintsche 2 and Kurt Engeland 1 1 Molecular Oncology, Medical School, University of Leipzig, 04103 Leipzig, Germany 2 Computational EvoDevo Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107 Leipzig, Germany Correspondence to: Gerd A. Müller, email: gerd.mueller@medizin.uni-leipzig.de Kurt Engeland, email: engeland@medizin.uni-leipzig.de Keywords: transcriptional repression, E2F, CHR transcriptional element, DREAM complex, p53 tumor suppressor Received: June 06, 2016 Accepted: June 28, 2016 Published: July 28, 2016 ABSTRACT A central question in cell cycle control is how differential gene expression is regulated. Timing of expression is important for correct progression through the cell cycle. E2F, CDE, and CHR promoter sites have been linked to transcriptional repression in resting cells and activation during the cell cycle. Further, the DREAM complex binds CHR or CDE/CHR elements of G 2 /M genes resulting in repression during G 0 /G 1 . Here, we show that DREAM also binds to E2F sites of S phase genes in quiescence and upon p53 activation. Furthermore, we describe a novel class of promoter sites, the CHR-like elements (CLE), which can support binding of DREAM to E2F elements. Activation of such S phase genes is achieved through binding of E2F1-3/DP complexes to E2F sites. In contrast, the activating MuvB complexes MMB and FOXM1-MuvB bind to CHR elements and mediate peak expression in G 2 /M. In conclusion, data presented here in combination with earlier results leads us to propose a model that explains how DREAM can repress early cell cycle genes through E2F or E2F/CLE sites and late genes through CHR or CDE/CHR elements. Also p53-dependent indirect transcriptional repression through the p53-p21-Cyclin/CDK-DREAM-E2F/CLE/CDE/CHR pathway requires DREAM binding to E2F or E2F/CLE sites in early cell cycle genes and binding of DREAM to CHR or CDE/CHR elements of late cell cycle genes. Specific timing of activation is achieved through binding of E2F1-3/DP to E2F sites and MMB or FOXM1-MuvB complexes to CHR elements.