title: The chromatin remodeller CHD8 is required for E2F-dependent transcription activation of S-phase genes.
abstract: The precise regulation of S-phase-specific genes is critical for cell proliferation. How the repressive chromatin configuration mediated by the retinoblastoma protein and repressor E2F factors changes at the G1/S transition to allow transcription activation is unclear. Here we show ChIP-on-chip studies that reveal that the chromatin remodeller CHD8 binds ∼ 2000 transcriptionally active promoters. The spectrum of CHD8 target genes was enriched in E2F-dependent genes. We found that CHD8 binds E2F-dependent promoters at the G1/S transition but not in quiescent cells. Consistently, CHD8 was required for G1/S-specific expression of these genes and for cell cycle re-entry on serum stimulation of quiescent cells. We also show that CHD8 interacts with E2F1 and, importantly, loading of E2F1 and E2F3, but not E2F4, onto S-specific promoters, requires CHD8. However, CHD8 recruiting is independent of these factors. Recruiting of MLL histone methyltransferase complexes to S-specific promoters was also severely impaired in the absence of CHD8. Furthermore, depletion of CHD8 abolished E2F1 overexpression-dependent S-phase stimulation of serum-starved cells, highlighting the essential role of CHD8 in E2F-dependent transcription activation.
authors.affiliation: Molecular Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Av. Americo Vespucio 41092 Seville, Spain, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Spain and Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Subtil-Rodríguez
authors.forename: Elena
authors.initials: E
authors.lastname: Vázquez-Chávez
authors.forename: María
authors.initials: M
authors.lastname: Ceballos-Chávez
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Paredes
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: José C
authors.initials: JC
authors.lastname: Reyes
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D016196:S Phase / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C523331:CHD8 protein, human; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D014157:Transcription Factors