Modeling Cooperative Gene Regulation Using Fast Orthogonal Search

Gene regulation is a complex and relatively poorly understood process. While a number of methods have suggested means by which gene transcription is activated, there are factors at work that no model has been able to fully explain. In eukaryotes, gene regulation is quite complex, so models have primarily focused on a relatively simple species, Saccharomyces cerevisiae. Because of the inherent complexity in higher species, and even in yeast, a method of identifying transcription factor (TF) binding motifs must be efficient and thorough in its analysis. Here we propose a method using the very efficient Fast Orthogonal Search (FOS) algorithm in order to uncover motifs as well as cooperatively binding groups of motifs that can explain variations in gene expression. The algorithm is very fast, exploring a motif list and constructing a final model within seconds or a few minutes, produces model terms that are consistent with known motifs while also revealing new motifs and interactions, and causes impressive reduction in variance with relatively few model terms over the cell cycle.

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Faculty Opinions recommendation of A competitive transcription factor binding mechanism determines the timing of late cell cycle-dependent gene expression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2947957.5387054 ◽

2010 ◽

Author(s):

Robert De Bruin

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Transcription Factor ◽

Transcription Factor Binding ◽

Binding Mechanism ◽

Factor Binding ◽

Cycle Dependent

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Transcription Factor–DNA Binding Motifs in Saccharomyces cerevisiae: Tools and Resources

Cold Spring Harbor Protocols ◽

10.1101/pdb.top080622 ◽

2016 ◽

Vol 2016 (11) ◽

pp. pdb.top080622 ◽

Cited By ~ 2

Author(s):

Joshua L. Schipper ◽

Raluca M. Gordân

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Dna Binding ◽

Binding Motifs ◽

Dna Binding Motifs

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Signal Transducer and Activator of Transcription (Stat) 5b-Mediated Inhibition of Insulin-Like Growth Factor Binding Protein-1 Gene Transcription: A Mechanism for Repression of Gene Expression by Growth Hormone

Molecular Endocrinology ◽

10.1210/me.2006-0543 ◽

2007 ◽

Vol 21 (6) ◽

pp. 1443-1457 ◽

Cited By ~ 26

Author(s):

Mitsuru Ono ◽

Dennis J. Chia ◽

Roxana Merino-Martinez ◽

Amilcar Flores-Morales ◽

Terry G. Unterman ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Gene Transcription ◽

Binding Protein ◽

Critical Role ◽

Somatic Growth ◽

Transcript Profiling ◽

Signal Transducer ◽

Igf Binding ◽

Igf Binding Protein

Abstract GH plays a central role in controlling somatic growth, tissue regeneration, and intermediary metabolism in most vertebrate species through mechanisms dependent on the regulation of gene expression. Recent studies using transcript profiling have identified large cohorts of genes whose expression is induced by GH. Other results have demonstrated that signal transducer and activator of transcription (Stat) 5b, a latent transcription factor activated by the GH receptor-associated protein kinase, Jak2, is a key agent in the GH-stimulated gene activation that leads to somatic growth. By contrast, little is known about the steps through which GH-initiated signaling pathways reduce gene expression. Here we show that Stat5b plays a critical role in the GH-regulated inhibition of IGF binding protein-1 gene transcription by impairing the actions of the FoxO1 transcription factor on the IGF binding protein-1 promoter. Additional observations using transcript profiling in the liver indicate that Stat5b may be a general mediator of GH-initiated gene repression. Our results provide a model for understanding how GH may simultaneously stimulate and inhibit the expression of different cohorts of genes via the same transcription factor, potentially explaining how GH action leads to integrated biological responses in the whole organism.

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Role of heat shock transcription factor in yeast metallothionein gene expression

Molecular and Cellular Biology ◽

10.1128/mcb.11.7.3676-3681.1991 ◽

1991 ◽

Vol 11 (7) ◽

pp. 3676-3681

Author(s):

W M Yang ◽

W Gahl ◽

D Hamer

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Heat Shock ◽

Gene Transcription ◽

Heat Shock Factor ◽

Heat Shock Transcription Factor ◽

Wild Type ◽

Promoter Sequences ◽

Metallothionein Gene ◽

Upstream Promoter

The induction of Saccharomyces cerevisiae metallothionein gene transcription by Cu and Ag is mediated by the ACE1 transcription factor. In an effort to detect additional stimuli and factors that regulate metallothionein gene transcription, we isolated a Cu-resistant suppressor mutant of an ACE1 deletion strain. Even in the absence of metals, the suppressor mutant exhibited high basal levels of metallothionein gene transcription that required upstream promoter sequences. The suppressor gene was cloned, and its predicted product was shown to correspond to yeast heat shock transcription factor with a single-amino-acid substitution in the DNA-binding domain. The mutant heat shock factor bound strongly to metallothionein gene upstream promoter sequences, whereas wild-type heat shock factor interacted weakly with the same region. Heat treatment led to a slight but reproducible induction of metallothionein gene expression in both wild-type and suppressor strains, and Cd induced transcription in the mutant strain. These studies provide evidence for multiple pathways of metallothionein gene transcriptional regulation in S. cerevisiae.

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Predicting transcription factor binding motifs from DNA-binding domains, chromatin accessibility and gene expression data

Nucleic Acids Research ◽

10.1093/nar/gkx358 ◽

2017 ◽

Vol 45 (10) ◽

pp. 5666-5677 ◽

Cited By ~ 5

Author(s):

Mahdi Zamanighomi ◽

Zhixiang Lin ◽

Yong Wang ◽

Rui Jiang ◽

Wing Hung Wong

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Dna Binding ◽

Gene Expression Data ◽

Chromatin Accessibility ◽

Expression Data ◽

Binding Motifs ◽

Dna Binding Domains ◽

Binding Domains ◽

Transcription Factor Binding Motifs

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Identification of a new set of cell cycle-regulatory genes that regulate S-phase transcription of histone genes in Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.12.11.5249-5259.1992 ◽

1992 ◽

Vol 12 (11) ◽

pp. 5249-5259 ◽

Cited By ~ 1

Author(s):

H Xu ◽

U J Kim ◽

T Schuster ◽

M Grunstein

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Dna Replication ◽

Gene Transcription ◽

S Phase ◽

Histone Gene ◽

Mrna Synthesis ◽

Histone Mrna ◽

Complementation Groups ◽

Histone Gene Transcription

Histone mRNA synthesis is tightly regulated to S phase of the yeast Saccharomyces cerevisiae cell cycle as a result of transcriptional and posttranscriptional controls. Moreover, histone gene transcription decreases rapidly if DNA replication is inhibited by hydroxyurea or if cells are arrested in G1 by the mating pheromone alpha-factor. To identify the transcriptional controls responsible for cycle-specific histone mRNA synthesis, we have developed a selection for mutations which disrupt this process. Using this approach, we have isolated five mutants (hpc1, hpc2, hpc3, hpc4, and hpc5) in which cell cycle regulation of histone gene transcription is altered. All of these mutations are recessive and belong to separate complementation groups. Of these, only one (hpc1) falls in one of the three complementation groups identified previously by other means (M. A. Osley and D. Lycan, Mol. Cell. Biol. 7:4204-4210, 1987), indicating that at least seven different genes are involved in the cell cycle-specific regulation of histone gene transcription. hpc4 is unique in that derepression occurs only in the presence of hydroxyurea but not alpha-factor, suggesting that at least one of the regulatory factors is specific to histone gene transcription after DNA replication is blocked. One of the hpc mutations (hpc2) suppresses delta insertion mutations in the HIS4 and LYS2 loci. This effect allowed the cloning and sequence analysis of HPC2, which encodes a 67.5-kDa, highly charged basic protein.

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A Bayesian Approach for Integrating Transcription Regulation and Gene Expression: Application to Saccharomyces Cerevisiae Cell Cycle Data

Systems Biology and Regulatory Genomics - Lecture Notes in Computer Science ◽

10.1007/978-3-540-48540-7_15 ◽

2007 ◽

pp. 178-187

Author(s):

Sudhakar Jonnalagadda ◽

Rajagopalan Srinivasan

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Transcription Regulation ◽

Bayesian Approach

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Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38

Nature Communications ◽

10.1038/s41467-020-19582-3 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Klára Kirsch ◽

András Zeke ◽

Orsolya Tőke ◽

Péter Sok ◽

Ashish Sethi ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Binding Sites ◽

Mechanistic Modeling ◽

Environmental Cues ◽

Phosphorylation Sites ◽

Binding Motifs ◽

Mitogen Activated Protein Kinases ◽

Transactivation Domains ◽

Mitogen Activated Protein

AbstractTranscription factor phosphorylation at specific sites often activates gene expression, but how environmental cues quantitatively control transcription is not well-understood. Activating protein 1 transcription factors are phosphorylated by mitogen-activated protein kinases (MAPK) in their transactivation domains (TAD) at so-called phosphoswitches, which are a hallmark in response to growth factors, cytokines or stress. We show that the ATF2 TAD is controlled by functionally distinct signaling pathways (JNK and p38) through structurally different MAPK binding sites. Moreover, JNK mediated phosphorylation at an evolutionarily more recent site diminishes p38 binding and made the phosphoswitch differently sensitive to JNK and p38 in vertebrates. Structures of MAPK-TAD complexes and mechanistic modeling of ATF2 TAD phosphorylation in cells suggest that kinase binding motifs and phosphorylation sites line up to maximize MAPK based co-regulation. This study shows how the activity of an ancient transcription controlling phosphoswitch became dependent on the relative flux of upstream signals.

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Determination of the Global Pattern of Gene Expression in Yeast Cells by Intracellular Levels of Guanine Nucleotides

mBio ◽

10.1128/mbio.02500-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Andy Hesketh ◽

Marta Vergnano ◽

Stephen G. Oliver

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Carbon Source ◽

Gene Transcription ◽

Adenine Nucleotide ◽

High Energy ◽

Yeast Cells ◽

Purine Nucleotides ◽

Global Pattern ◽

Content Type

ABSTRACT Correlations between gene transcription and the abundance of high-energy purine nucleotides in Saccharomyces cerevisiae have often been noted. However, there has been no systematic investigation of this phenomenon in the absence of confounding factors such as nutrient status and growth rate, and there is little hard evidence for a causal relationship. Whether transcription is fundamentally responsive to prevailing cellular energetic conditions via sensing of intracellular purine nucleotides, independently of specific nutrition, remains an important question. The controlled nutritional environment of chemostat culture revealed a strong correlation between ATP and GTP abundance and the transcription of genes required for growth. Short pathways for the inducible and futile consumption of ATP or GTP were engineered into S. cerevisiae, permitting analysis of the transcriptional effect of an increased demand for these nucleotides. During steady-state growth using the fermentable carbon source glucose, the futile consumption of ATP led to a decrease in intracellular ATP concentration but an increase in GTP and the guanylate energy charge (GEC). Expression of transcripts encoding proteins involved in ribosome biogenesis, and those controlled by promoters subject to SWI/SNF-dependent chromatin remodelling, was correlated with these nucleotide pool changes. Similar nucleotide abundance changes were observed using a nonfermentable carbon source, but an effect on the growth-associated transcriptional programme was absent. Induction of the GTP-cycling pathway had only marginal effects on nucleotide abundance and gene transcription. The transcriptional response of respiring cells to glucose was dampened in chemostats induced for ATP cycling, but not GTP cycling, and this was primarily associated with altered adenine nucleotide levels. IMPORTANCE This paper investigates whether, independently of the supply of any specific nutrient, gene transcription responds to the energy status of the cell by monitoring ATP and GTP levels. Short pathways for the inducible and futile consumption of ATP or GTP were engineered into the yeast Saccharomyces cerevisiae, and the effect of an increased demand for these purine nucleotides on gene transcription was analyzed. The resulting changes in transcription were most consistently associated with changes in GTP and GEC levels, although the reprogramming in gene expression during glucose repression is sensitive to adenine nucleotide levels. The results show that GTP levels play a central role in determining how genes act to respond to changes in energy supply and that any comprehensive understanding of the control of eukaryotic gene expression requires the elucidation of how changes in guanine nucleotide abundance are sensed and transduced to alter the global pattern of transcription.

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