Fkh1 and Fkh2 bind multiple chromosomal elements in the S. cerevisiae genome with distinct specificities and cell cycle dynamics.
Fkh1 and Fkh2 bind multiple chromosomal elements in the S. cerevisiae genome with distinct specificities and cell cycle dynamics.
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DOI：
10.1371/journal.pone.0087647
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Aparicio OM
中科院分区：
文献类型：
--
作者：
Ostrow AZ;Nellimoottil T;Knott SR;Fox CA;Tavaré S;Aparicio OM
叉头盒（FOX）转录因子在高等真核生物中调节多种细胞功能，包括细胞周期控制和发育调节。在酿酒酵母中，Forkhead蛋白Fkh1和Fkh2具有类似的功能，调节参与细胞周期控制的基因，同时也调节参与配子发育的交配型沉默和开关。最近，我们发现Fkh1和Fkh2在调控复制起始时间中的新作用，就像交配型转换中的供体偏好一样，似乎涉及远程染色体相互作用，这表明Fkh1和Fkh2在染色质结构和组织中起作用。为了阐明Fkh1和Fkh2如何调控其靶DNA元件并潜在地调控基因组的空间组织，我们使用ChIP-chip芯片对Fkh1和Fkh2染色质结合进行了全基因组分析。我们的研究结果证实并扩展了先前的发现，即Fkh1和Fkh2控制细胞周期调节基因的表达。此外，数据揭示了数百个仅结合Fkh1的新位点，并且与同时结合Fkh1和Fkh2的位点表现出不同的染色质结构。研究结果还表明，Fkh1在早期启动复制的复制起点子集的调控中起主要作用，并且Fkh1/2与这些位点的结合是细胞周期调控的。最后，我们证明Fkh1和Fkh2与多种遗传元件结合，包括着丝粒和Pol iii转录的snorna和trna，极大地扩展了它们潜在的功能靶标库，这与它们最近提出的介导基因组空间组织的作用一致。
Forkhead box (FOX) transcription factors regulate a wide variety of cellular functions in higher eukaryotes, including cell cycle control and developmental regulation. In Saccharomyces cerevisiae, Forkhead proteins Fkh1 and Fkh2 perform analogous functions, regulating genes involved in cell cycle control, while also regulating mating-type silencing and switching involved in gamete development. Recently, we revealed a novel role for Fkh1 and Fkh2 in the regulation of replication origin initiation timing, which, like donor preference in mating-type switching, appears to involve long-range chromosomal interactions, suggesting roles for Fkh1 and Fkh2 in chromatin architecture and organization. To elucidate how Fkh1 and Fkh2 regulate their target DNA elements and potentially regulate the spatial organization of the genome, we undertook a genome-wide analysis of Fkh1 and Fkh2 chromatin binding by ChIP-chip using tiling DNA microarrays. Our results confirm and extend previous findings showing that Fkh1 and Fkh2 control the expression of cell cycle-regulated genes. In addition, the data reveal hundreds of novel loci that bind Fkh1 only and exhibit a distinct chromatin structure from loci that bind both Fkh1 and Fkh2. The findings also show that Fkh1 plays the predominant role in the regulation of a subset of replication origins that initiate replication early, and that Fkh1/2 binding to these loci is cell cycle-regulated. Finally, we demonstrate that Fkh1 and Fkh2 bind proximally to a variety of genetic elements, including centromeres and Pol III-transcribed snoRNAs and tRNAs, greatly expanding their potential repertoire of functional targets, consistent with their recently suggested role in mediating the spatial organization of the genome.
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