Control of Transcriptional Variability by Overlapping Feed-Forward Regulatory Motifs

Abstract

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.

Role of the Histone Variant H2A.Z/Htz1p in TBP Recruitment, Chromatin Dynamics, and Regulated Expression of Oleate-Responsive Genes

“…The exposure of yeast cells to oleate results in a large-scale reorganization of gene expression regulatory networks and provides an excellent experimental system for understanding the mechanisms of gene expression at both the molecular and network levels (28,33). The resulting changes in gene expression are widespread, representing the reorganization of regulatory networks governing numerous categories of gene function.…”

Integrated Phosphoproteomics Analysis of a Signaling Network Governing Nutrient Response and Peroxisome Induction

“…Indeed, like Pip2p, the phosphorylation of Cst6p modulates the response of oleateinduced genes; however, it appears that these posttranslational modifications play different time-dependent roles. As the transcriptional regulation of oleate-induced peroxisome proliferation is used as a paradigm for understanding transcriptional network dynamics, it will be important to incorporate these new insights into future models (3,4,(47)(48)(49).…”

“…Pip2p is a well characterized central regulator of oleate-responsive loci but has not been previously reported to be phosphorylated, and models of the transcriptional response involving Pip2p do not consider its potential posttranslational modifications (3,4). Phosphorylated Pip2p was enriched in oleate-induced conditions but barely above the statistical cutoff used.…”

“…In yeast, genes encoding abundant peroxisomal proteins are repressed in cells grown in glucose and highly induced in response to FA. The induction process involves global reorganization of transcriptional networks and activities (3,4), peroxisome proliferation (5) (a process that highlights the dynamic nature of the peroxisomal proteome (6, 7)), and a host of additional coordinated cellular responses such as alterations to the cell cycle, cytoskeleton, membrane dynamics, and chromatin. Signaling molecules are key regulators of these complex and coordinate responses.…”

A self-propelled biological process

“…A type of this forward control system, called feedforward loop, in which "A" turns on "B" and the action of "A" and "B" is integrated to turn on "C," has been observed in transcriptional regulatory networks in yeast and bacteria and in the metabolic network of glycolysis in human erythrocytes. [1][2][3][4][5] Whether other intracellular processes also exploit a feedforward cooperativity remains to be further investigated.…”