title: Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae.
abstract: The replication of eukaryotic chromosomes is organized temporally and spatially within the nucleus through epigenetic regulation of replication origin function. The characteristic initiation timing of specific origins is thought to reflect their chromatin environment or sub-nuclear positioning, however the mechanism remains obscure. Here we show that the yeast Forkhead transcription factors, Fkh1 and Fkh2, are global determinants of replication origin timing. Forkhead regulation of origin timing is independent of local levels or changes of transcription. Instead, we show that Fkh1 and Fkh2 are required for the clustering of early origins and their association with the key initiation factor Cdc45 in G1 phase, suggesting that Fkh1 and Fkh2 selectively recruit origins to emergent replication factories. Fkh1 and Fkh2 bind Fkh-activated origins, and interact physically with ORC, providing a plausible mechanism to cluster origins. These findings add a new dimension to our understanding of the epigenetic basis for differential origin regulation and its connection to chromosomal domain organization.
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Simon R V
authors.initials: SR
authors.lastname: Knott
authors.forename: Jared M
authors.initials: JM
authors.lastname: Peace
authors.forename: A Zachary
authors.initials: AZ
authors.lastname: Ostrow
authors.forename: Yan
authors.initials: Y
authors.lastname: Gan
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Rex
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Viggiani
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Aparicio
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016193:G1 Phase; D009687:Nuclear Proteins / Q000378:metabolism; D018741:Replication Origin; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C102209:CDC45 protein, S cerevisiae; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C464906:Fkh1 protein, S cerevisiae; C464958:Fkh2 protein, S cerevisiae; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins