Forkhead Transcription Factors Establish Origin Timing and Long-Range Clustering in S. cerevisiae

• Published in: Cell Vol. 148; no. 1-2; pp. 99 - 111
• Main Authors: Knott, Simon R.V., Peace, Jared M., Ostrow, A. Zachary, Gan, Yan, Rex, Alexandra E., Viggiani, Christopher J., Tavaré, Simon, Aparicio, Oscar M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2012
• Subjects: Cell Cycle Proteins - metabolism; chromatin; DNA-Binding Proteins - metabolism; epigenetics; Forkhead Transcription Factors - metabolism; G1 Phase; interphase; Nuclear Proteins - metabolism; replication; Replication Origin; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; transcription factors; Transcription, Genetic; yeasts
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.12.012

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. [Display omitted] ► Yeast Fox transcription factors, Fkh1/2, regulate early replication origin firing ► Fkh1/2 regulate origin timing independently of transcriptional effects ► In G1 phase Fkh1/2 are required for early origin clustering and Cdc45 association ► Fkh1/2 physically interact with the Origin Recognition Complex Forkhead transcription factors bind to replication origins. Rather than promoting transcription at these sites, they facilitate the clustering of these origins and their association with a replication initiation factor, promoting early firing.