A Quantitative Model of Transcription Factor-activated Gene Expression

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2008 Oct 14

PMID 18849996

Citations 85

Authors

Harold D Kim

Erin K OShea

Affiliations

Soon will be listed here.

Abstract

A challenge facing biology is to develop quantitative, predictive models of gene regulation. Eukaryotic promoters contain transcription factor binding sites of differing affinity and accessibility, but we understand little about how these variables combine to generate a fine-tuned, quantitative transcriptional response. Here we used the PHO5 promoter in budding yeast to quantify the relationship between transcription factor input and gene expression output, termed the gene-regulation function (GRF). A model that captures variable interactions between transcription factors, nucleosomes and the promoter faithfully reproduced the observed quantitative changes in the GRF that occur upon altering the affinity of transcription factor binding sites, and implicates nucleosome-modulated accessibility of transcription factor binding sites in increasing the diversity of gene expression profiles. This work establishes a quantitative framework that can be applied to predict GRFs of other eukaryotic genes.

Citing Articles

Thermodynamic principles link transcription factor affinities to single-molecule chromatin states in cells.

Schaepe J, Fries T, Doughty B, Crocker O, Hinks M, Marklund E bioRxiv. 2025; .

PMID: 39975040 PMC: 11838358. DOI: 10.1101/2025.01.27.635162.

Single-molecule states link transcription factor binding to gene expression.

Doughty B, Hinks M, Schaepe J, Marinov G, Thurm A, Rios-Martinez C Nature. 2024; 636(8043):745-754.

PMID: 39567683 DOI: 10.1038/s41586-024-08219-w.

A DNA base-specific sequence interposed between CRX and NRL contributes to RHODOPSIN expression.

Maritato R, Medugno A, DAndretta E, De Riso G, Lupo M, Botta S Sci Rep. 2024; 14(1):26313.

PMID: 39487168 PMC: 11530525. DOI: 10.1038/s41598-024-76664-8.

MONITTR allows real-time imaging of transcription and endogenous proteins in C. elegans.

Liu X, Chang Z, Sun P, Cao B, Wang Y, Fang J J Cell Biol. 2024; 224(1).

PMID: 39400293 PMC: 11473600. DOI: 10.1083/jcb.202403198.

Live-cell analysis of IMPDH protein levels during yeast colony growth provides insights into the regulation of GTP synthesis.

Shand E, Sweeney K, Sundling K, McClean M, Brow D mBio. 2024; 15(8):e0102124.

PMID: 38940616 PMC: 11323793. DOI: 10.1128/mbio.01021-24.

References

Urlinger S, Baron U, Thellmann M, Hasan M, Bujard H, Hillen W . Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci U S A. 2000; 97(14):7963-8. PMC: 16653. DOI: 10.1073/pnas.130192197. View

Rosenfeld N, Young J, Alon U, Swain P, Elowitz M . Gene regulation at the single-cell level. Science. 2005; 307(5717):1962-5. DOI: 10.1126/science.1106914. View

Steger D, Haswell E, Miller A, Wente S, OShea E . Regulation of chromatin remodeling by inositol polyphosphates. Science. 2002; 299(5603):114-6. PMC: 1458531. DOI: 10.1126/science.1078062. View

Bintu L, Buchler N, Garcia H, Gerland U, Hwa T, Kondev J . Transcriptional regulation by the numbers: applications. Curr Opin Genet Dev. 2005; 15(2):125-35. PMC: 3462814. DOI: 10.1016/j.gde.2005.02.006. View

Becskei A, Kaufmann B, van Oudenaarden A . Contributions of low molecule number and chromosomal positioning to stochastic gene expression. Nat Genet. 2005; 37(9):937-44. DOI: 10.1038/ng1616. View

Adkins M, Tyler J . Transcriptional activators are dispensable for transcription in the absence of Spt6-mediated chromatin reassembly of promoter regions. Mol Cell. 2006; 21(3):405-16. DOI: 10.1016/j.molcel.2005.12.010. View

Jessen W, Hoose S, Kilgore J, Kladde M . Active PHO5 chromatin encompasses variable numbers of nucleosomes at individual promoters. Nat Struct Mol Biol. 2006; 13(3):256-63. DOI: 10.1038/nsmb1062. View

Nalley K, Johnston S, Kodadek T . Proteolytic turnover of the Gal4 transcription factor is not required for function in vivo. Nature. 2006; 442(7106):1054-7. DOI: 10.1038/nature05067. View

Yao J, Munson K, Webb W, Lis J . Dynamics of heat shock factor association with native gene loci in living cells. Nature. 2006; 442(7106):1050-3. DOI: 10.1038/nature05025. View

10.

Maerkl S, Quake S . A systems approach to measuring the binding energy landscapes of transcription factors. Science. 2007; 315(5809):233-7. DOI: 10.1126/science.1131007. View

11.

Zhang H, Reese J . Exposing the core promoter is sufficient to activate transcription and alter coactivator requirement at RNR3. Proc Natl Acad Sci U S A. 2007; 104(21):8833-8. PMC: 1885588. DOI: 10.1073/pnas.0701666104. View

12.

Adkins M, Williams S, Linger J, Tyler J . Chromatin disassembly from the PHO5 promoter is essential for the recruitment of the general transcription machinery and coactivators. Mol Cell Biol. 2007; 27(18):6372-82. PMC: 2099613. DOI: 10.1128/MCB.00981-07. View

13.

Cairns B . Chromatin remodeling: insights and intrigue from single-molecule studies. Nat Struct Mol Biol. 2007; 14(11):989-96. PMC: 2788559. DOI: 10.1038/nsmb1333. View

14.

Kalisky T, Dekel E, Alon U . Cost-benefit theory and optimal design of gene regulation functions. Phys Biol. 2007; 4(4):229-45. DOI: 10.1088/1478-3975/4/4/001. View

15.

Karpova T, Kim M, Spriet C, Nalley K, Stasevich T, Kherrouche Z . Concurrent fast and slow cycling of a transcriptional activator at an endogenous promoter. Science. 2008; 319(5862):466-9. DOI: 10.1126/science.1150559. View

16.

Segal E, Raveh-Sadka T, Schroeder M, Unnerstall U, Gaul U . Predicting expression patterns from regulatory sequence in Drosophila segmentation. Nature. 2008; 451(7178):535-40. DOI: 10.1038/nature06496. View

17.

Lam F, Steger D, OShea E . Chromatin decouples promoter threshold from dynamic range. Nature. 2008; 453(7192):246-50. PMC: 2435410. DOI: 10.1038/nature06867. View

18.

Boeger H, Griesenbeck J, Kornberg R . Nucleosome retention and the stochastic nature of promoter chromatin remodeling for transcription. Cell. 2008; 133(4):716-26. PMC: 2409070. DOI: 10.1016/j.cell.2008.02.051. View

19.

Barbaric S, Reinke H, Horz W . Multiple mechanistically distinct functions of SAGA at the PHO5 promoter. Mol Cell Biol. 2003; 23(10):3468-76. PMC: 164768. DOI: 10.1128/MCB.23.10.3468-3476.2003. View

20.

Boeger H, Griesenbeck J, Strattan J, Kornberg R . Nucleosomes unfold completely at a transcriptionally active promoter. Mol Cell. 2003; 11(6):1587-98. DOI: 10.1016/s1097-2765(03)00231-4. View