Control of transcriptional variability by overlapping feed-forward regulatory motifs
Control of transcriptional variability by overlapping feed-forward regulatory motifs
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DOI：
10.1529/biophysj.108.134064
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发表时间：
2008-10-15
影响因子：
3.4
通讯作者：
Aitchison, John D.
中科院分区：
文献类型：
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作者：
Ratushny, Alexander V.;Ramsey, Stephen A.;Aitchison, John D.
在酵母中，脂肪酸（FA）的β-氧化发生在过氧化物酶体中，过氧化物酶体是一种细胞器，其大小和数量受环境因素的控制。过氧化物酶体组装和功能所需的基因的表达由转录调控网络控制，该转录调控网络由FA如油酸诱导。核心FA响应转录网络由碳源敏感转录因子组成，通过重叠前馈网络基序（OFFNM）调节关键靶基因。然而，缺乏对这种网络结构在调节动态FA诱导的基因表达中的功能的系统水平的理解。OFFNM在调节油酸的动态和细胞群体转录响应中的特定作用使用由指示过氧化物酶体诱导的四个核心转录因子基因（ADR 1、OAF 1、PIP 2和OAF 3）和两个报告基因（CTA 1和POT 1）组成的动力学模型进行了研究。模型的模拟结果表明：1）Adr 1 p驱动的前馈回路降低了靶基因的稳态表达变异性，2）Oaf 3 p驱动的抑制性前馈回路调节了靶基因对油酸浓度的动态响应;和3），Oaf 1 p和Pip 2 p的异源二聚化在靶基因的油酸依赖性表达的背景下似乎不具有降噪功能。OFFNM在酵母调节组中高度过度表达，表明针对OFFNM描述的特定功能或该基序的其他性质提供了选择性优势。
In yeast, beta-oxidation of fatty acids (FAs) takes place in the peroxisome, an organelle whose size and number are controlled in response to environmental cues. The expression of genes required for peroxisome assembly and function is controlled by a transcriptional regulatory network that is induced by FAs such as oleate. The core FA-responsive transcriptional network consists of carbon source-sensing transcription factors that regulate key target genes through an overlapping feed-forward network motif (OFFNM). However, a systems-level understanding of the function of this network architecture in regulating dynamic FA-induced gene expression is lacking. The specific role of the OFFNM in regulating the dynamic and cell-population transcriptional response to oleate was investigated using a kinetic model comprised of four core transcription factor genes (ADR1, OAF1, PIP2, and OAF3) and two reporter genes ( CTA1 and POT1) that are indicative of peroxisome induction. Simulations of the model suggest that 1), the intrinsic Adr1p-driven feed-forward loop reduces the steady-state expression variability of target genes; 2), the parallel Oaf3p-driven inhibitory feed-forward loop modulates the dynamic response of target genes to a transiently varying oleate concentration; and 3), heterodimerization of Oaf1p and Pip2p does not appear to have a noise-reducing function in the context of oleate-dependent expression of target genes. The OFFNM is highly overrepresented in the yeast regulome, suggesting that the specific functions described for the OFFNM, or other properties of this motif, provide a selective advantage.