Transcription factor binding process is the primary driver of noise in gene expression

Noise in expression of individual genes gives rise to variations in activity of cellular pathways and generates heterogeneity in cellular phenotypes. Phenotypic heterogeneity has important implications for antibiotic persistence, mutation penetrance, cancer growth and therapy resistance. Specific molecular features such as the presence of the TATA box sequence and the promoter nucleosome occupancy have been associated with noise. However, the relative importance of these features in noise regulation is unclear and how well these features can predict noise has not yet been assessed. Here through an integrated statistical model of gene expression noise in yeast we found that the number of regulating transcription factors (TFs) of a gene was a key predictor of noise, whereas presence of the TATA box and the promoter nucleosome occupancy had poor predictive power. With an increase in the number of regulatory TFs, there was a rise in the number of cooperatively binding TFs. In addition, an increased number of regulatory TFs meant more overlaps in TF binding sites, resulting in competition between TFs for binding to the same region of the promoter. Through modeling of TF binding to promoter and application of stochastic simulations, we demonstrated that competition and cooperation among TFs could increase noise. Thus, our work uncovers a process of noise regulation that arises out of the dynamics of gene regulation and is not dependent on any specific transcription factor or specific promoter sequence.


STRE_elem
Presence/Absence of the Stress Response Element in the promoter [1] TATAbox presence/Absence of the TATAbox sequence in the promoter [

2] ConsensClustNum
Number of consensus clusters of transcription start sites [3] ClosestTSS Closest transcription start site to the coding region SpreadTSS Spread of potential transcription start sites MedPromShapeScore Median promoter shape score tAI_full tRNA adaptation index for the full gene [4]  Number of sites between 300 bp and 400bp upstream of the start codon occupied by nucleosomes N_PrNO500 Number of sites between 400 bp and 500bp upstream of the start codon occupied by nucleosomes N_PrNO600 Number of sites between 500 bp and 600bp upstream of the start codon occupied by nucleosomes N_PrNO700 Number of sites between 600 bp and 700bp upstream of the start codon occupied by nucleosomes N_PrNO800 Number of sites between 700 bp and 800bp upstream of the start codon occupied by nucleosomes N_PrNO900 Number of sites between 800 bp and 900bp upstream of the start codon occupied by nucleosomes N_PrNO1000 Number of sites between 900 bp and 1000bp upstream of the start codon occupied by nucleosomes

V_PrNO50
Level of absolute nucleosome occupancy in the region upto 50bp upstream of the start codon V_PrNO100 Level of absolute nucleosome occupancy in the region between 50bp and 100bp upstream of the start codon

V_PrNO150
Level of absolute nucleosome occupancy in the region between 100bp and 150bp upstream of the start codon V_PrNO200 Level of absolute nucleosome occupancy in the region between 150bp and 200bp upstream of the start codon V_PrNO300 Level of absolute nucleosome occupancy in the region between 200bp and 300bp upstream of the start codon V_PrNO400 Level of absolute nucleosome occupancy in the region between 300bp and 400bp upstream of the start codon V_PrNO500 Level of absolute nucleosome occupancy in the region between 400bp and 500bp upstream of the start codon V_PrNO600 Level of absolute nucleosome occupancy in the region between 500bp and 600bp upstream of the start codon V_PrNO700 Level of absolute nucleosome occupancy in the region between 600bp and 700bp upstream of the start codon V_PrNO800 Level of absolute nucleosome occupancy in the region between 700bp and 800bp upstream of the start codon V_PrNO900 Level of absolute nucleosome occupancy in the region between 800bp and 900bp upstream of the start codon V_PrNO1000 Level of absolute nucleosome occupancy in the region between 900bp and 1000bp upstream of the start codon NumGb_H3 Number of sites in the genebody occupied by H3 Level of H3 in the genebody NumGb_H4 Number of sites in the genebody occupied by H4 Gb_H4 Level of H4 in the genebody NumGb_H3K9ac_vsH3 Number of sites in the genebody showing H3K9ac modification Gb_H3K9ac_vsH3 Level of H3K9ac modification in the genebody Number of sites in the promoter occupied by H3 Prom_H3 Level of H3 in the promoter NumProm_H4 Number of sites in the promoter occupied by H4 Prom_H4 Level of H4 in the promoter NumProm_H3K9ac_vsH3 Number of sites in the promoter showing H3K9ac modification Prom_H3K9ac_vsH3 Level of H3K9ac modification in the promoter NumProm_H3K14ac_vsH3 Number of sites in the promoter showing H3K14ac modification Prom_H3K14ac_vsH3 Level of H3K14ac modification in the promoter NumProm_H4ac_vsH3 Number of sites in the promoter showing H4ac modification Prom_H4ac_vsH3 Level of H4ac modification in the promoter Level of H3K79me3 modification in the promoter NumProm_ESA1 Number of sites in the promoter showing ESA1 binding Prom_ESA1 Level of ESA1 binding in the promoter NumProm_GCN5 Number of sites in the promoter showing GCN5 binding Prom_GCN5 Level of GCN5 binding in the promoter NumProm_GCN4.AA Number of sites in the promoter showing GCN4 binding Prom_GCN4.AA Level of GCN4 binding in the promoter DionScience2007_Gene_G1Lambda H3 turnover rate in the coding region of G1 arrested yeast [7] DionScience2007_Gene_G1Lambda_Zsco re H3 turnover rate in the coding region of G1 arrested yeast (Z-score calculated)

DionScience2007_Prom_G1Lambda
H3 turnover rate in the promoter region of G1 arrested yeast DionScience2007_Prom_G1Lambda_Zsco re H3 turnover rate in the promoter region of G1 arrested yeast (Z-score calculated)

DionScience2007_Gene_H3Occ
H3 occupancy in the coding region DionScience2007_Gene_NucOcc Nucleosome occupancy in the coding region DionScience2007_Prom_H3Occ H3 occupancy in the promoter region DionScience2007_Prom_NucOcc Nucleosome occupancy in the promoter region DionScience2007_Gene_PolII_t0 RNA pol II occupancy in the coding region at t=0 DionScience2007_Gene_PolII_t60 RNA pol II occupancy in the coding region at t=60 mins DionScience2007_Prom_PolIII_t0 RNA pol II occupancy in the promoter region at t=0 DionScience2007_Prom_PolIII_t60 RNA pol II occupancy in the promoter region at t=60 mins Sun2012_mRNA_Synth_rate mRNA synthesis rate mRNA decay rate mRNA_PARS1 mRNA secondary structure PARS score of the first codon [9] mRNA_PARS3 mRNA secondary structure PARS score of the first three codons mRNA_PARS5 mRNA secondary structure PARS score of the first five codons mRNA_PARS10 mRNA secondary structure PARS score of the first ten codons mRNA_PARS15 mRNA secondary structure PARS score of the first fifteen codons mRNA_PARS20 mRNA secondary structure PARS score of the first twenty codons mRNA_PARS25 mRNA secondary structure PARS score of the first twenty-five codons  Level of H3K9ac modifications in TF binding sites TFsiteH3K14ac_vsH3 Level of H3K14ac modifications in TF binding sites TFsiteH4ac_vsH3 Level of H4ac modifications in TF binding sites TFsiteH3K4me1_vsH3 Level of H3K4me1 modifications in TF binding sites TFsiteH3K4me2_vsH3 Level of H3K4me2 modifications in TF binding sites TFsiteH3K4me3_vsH3 Level of H3K4me3 modifications in TF binding sites TFsiteH3K36me3_vsH3 Level of H3K36me3 modifications in TF binding sites TFsiteH3K79me3_vsH3 Level of H3K79me3 modifications in TF binding sites TFsiteESA1 Level of ESA1 in TF binding sites TFsiteGCN5 Level of GCN5 in TF binding sites TFsiteGCN4.AA Level of GCN4 in TF binding sites

PercOfPromH3
Percentage of the total promoter H3 level observed in the TF binding sites

GSE44200_10MNase_Mot1TBPrat_Gene
Ratio of Mot1 to TBP occupancy in the coding region (results from 10min Mnase treatment) GSE44200_10MNase_TBPocc_Prom TBP occupancy in the promoter region (results from 10min Mnase treatment)

GSE44200_10MNase_Mot1occ_Prom
Mot1 occupancy in the promoter region (results from 10min Mnase treatment)