Eukaryotic Transcription Factors Can Track and Control Their Target Genes Using DNA Antennas

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jan 30

PMID 31992709

Citations 23

Authors

Milagros Castellanos

Nivin Mothi

Victor Munoz

Affiliations

Soon will be listed here.

Abstract

Eukaryotic transcription factors (TF) function by binding to short 6-10 bp DNA recognition sites located near their target genes, which are scattered through vast genomes. Such process surmounts enormous specificity, efficiency and celerity challenges using a molecular mechanism that remains poorly understood. Combining biophysical experiments, theory and bioinformatics, we dissect the interplay between the DNA-binding domain of Engrailed, a Drosophila TF, and the regulatory regions of its target genes. We find that Engrailed binding affinity is strongly amplified by the DNA regions flanking the recognition site, which contain long tracts of degenerate recognition-site repeats. Such DNA organization operates as an antenna that attracts TF molecules in a promiscuous exchange among myriads of intermediate affinity binding sites. The antenna ensures a local TF supply, enables gene tracking and fine control of the target site's basal occupancy. This mechanism illuminates puzzling gene expression data and suggests novel engineering strategies to control gene expression.

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References

Milo R, Jorgensen P, Moran U, Weber G, Springer M . BioNumbers--the database of key numbers in molecular and cell biology. Nucleic Acids Res. 2009; 38(Database issue):D750-3. PMC: 2808940. DOI: 10.1093/nar/gkp889. View

Berg O, Winter R, von Hippel P . Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory. Biochemistry. 1981; 20(24):6929-48. DOI: 10.1021/bi00527a028. View

Blainey P, Luo G, Kou S, Mangel W, Verdine G, Bagchi B . Nonspecifically bound proteins spin while diffusing along DNA. Nat Struct Mol Biol. 2009; 16(12):1224-9. PMC: 2889498. DOI: 10.1038/nsmb.1716. View

Wang Y, Austin R, Cox E . Single molecule measurements of repressor protein 1D diffusion on DNA. Phys Rev Lett. 2006; 97(4):048302. DOI: 10.1103/PhysRevLett.97.048302. View

Gorman J, Greene E . Visualizing one-dimensional diffusion of proteins along DNA. Nat Struct Mol Biol. 2008; 15(8):768-74. DOI: 10.1038/nsmb.1441. View

Esadze A, Kemme C, Kolomeisky A, Iwahara J . Positive and negative impacts of nonspecific sites during target location by a sequence-specific DNA-binding protein: origin of the optimal search at physiological ionic strength. Nucleic Acids Res. 2014; 42(11):7039-46. PMC: 4066804. DOI: 10.1093/nar/gku418. View

Elf J, Li G, Xie X . Probing transcription factor dynamics at the single-molecule level in a living cell. Science. 2007; 316(5828):1191-4. PMC: 2853898. DOI: 10.1126/science.1141967. View

Felsenfeld G . Chromatin unfolds. Cell. 1996; 86(1):13-9. DOI: 10.1016/s0092-8674(00)80073-2. View

Cairns B . The logic of chromatin architecture and remodelling at promoters. Nature. 2009; 461(7261):193-8. DOI: 10.1038/nature08450. View

10.

Jones P, Takai D . The role of DNA methylation in mammalian epigenetics. Science. 2001; 293(5532):1068-70. DOI: 10.1126/science.1063852. View

11.

Badis G, Berger M, Philippakis A, Talukder S, Gehrke A, Jaeger S . Diversity and complexity in DNA recognition by transcription factors. Science. 2009; 324(5935):1720-3. PMC: 2905877. DOI: 10.1126/science.1162327. View

12.

Davidson E . Emerging properties of animal gene regulatory networks. Nature. 2010; 468(7326):911-20. PMC: 3967874. DOI: 10.1038/nature09645. View

13.

Biggin M . Animal transcription networks as highly connected, quantitative continua. Dev Cell. 2011; 21(4):611-26. DOI: 10.1016/j.devcel.2011.09.008. View

14.

Ptashne M, Gann A . Transcriptional activation by recruitment. Nature. 1997; 386(6625):569-77. DOI: 10.1038/386569a0. View

15.

Zinzen R, Girardot C, Gagneur J, Braun M, Furlong E . Combinatorial binding predicts spatio-temporal cis-regulatory activity. Nature. 2009; 462(7269):65-70. DOI: 10.1038/nature08531. View

16.

Yanez-Cuna J, Dinh H, Kvon E, Shlyueva D, Stark A . Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding. Genome Res. 2012; 22(10):2018-30. PMC: 3460196. DOI: 10.1101/gr.132811.111. View

17.

Yang A, Zhu Z, Kapranov P, McKeon F, Church G, Gingeras T . Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol Cell. 2006; 24(4):593-602. DOI: 10.1016/j.molcel.2006.10.018. View

18.

Hu Z, Killion P, Iyer V . Genetic reconstruction of a functional transcriptional regulatory network. Nat Genet. 2007; 39(5):683-7. DOI: 10.1038/ng2012. View

19.

Chen J, Zhang Z, Li L, Chen B, Revyakin A, Hajj B . Single-molecule dynamics of enhanceosome assembly in embryonic stem cells. Cell. 2014; 156(6):1274-1285. PMC: 4040518. DOI: 10.1016/j.cell.2014.01.062. View

20.

Natarajan A, Yardimci G, Sheffield N, Crawford G, Ohler U . Predicting cell-type-specific gene expression from regions of open chromatin. Genome Res. 2012; 22(9):1711-22. PMC: 3431488. DOI: 10.1101/gr.135129.111. View