Identification of Upstream Transcription Factor Binding Sites in Orthologous Genes Using Mixed Student's T-test Statistics

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2022 Jun 7

PMID 35671296

Authors

Tinghua Huang

Hong Xiao

Qi Tian

Zhen He

Cheng Yuan

Zezhao Lin

Xuejun Gao

Min Yao

Affiliations

Soon will be listed here.

Abstract

Background: Transcription factor (TF) regulates the transcription of DNA to messenger RNA by binding to upstream sequence motifs. Identifying the locations of known motifs in whole genomes is computationally intensive.

Methodology/principal Findings: This study presents a computational tool, named "Grit", for screening TF-binding sites (TFBS) by coordinating transcription factors to their promoter sequences in orthologous genes. This tool employs a newly developed mixed Student's t-test statistical method that detects high-scoring binding sites utilizing conservation information among species. The program performs sequence scanning at a rate of 3.2 Mbp/s on a quad-core Amazon server and has been benchmarked by the well-established ChIP-Seq datasets, putting Grit amongst the top-ranked TFBS predictors. It significantly outperforms the well-known transcription factor motif scanning tools, Pscan (4.8%) and FIMO (17.8%), in analyzing well-documented ChIP-Atlas human genome Chip-Seq datasets.

Significance: Grit is a good alternative to current available motif scanning tools.

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References

Warner J, Philippakis A, Jaeger S, He F, Lin J, Bulyk M . Systematic identification of mammalian regulatory motifs' target genes and functions. Nat Methods. 2008; 5(4):347-53. PMC: 2708972. DOI: 10.1038/nmeth.1188. View

Schneider T, Stormo G, Gold L, Ehrenfeucht A . Information content of binding sites on nucleotide sequences. J Mol Biol. 1986; 188(3):415-31. DOI: 10.1016/0022-2836(86)90165-8. View

Fornes O, Castro-Mondragon J, Khan A, van der Lee R, Zhang X, Richmond P . JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2019; 48(D1):D87-D92. PMC: 7145627. DOI: 10.1093/nar/gkz1001. View

Elkon R, Linhart C, Sharan R, Shamir R, Shiloh Y . Genome-wide in silico identification of transcriptional regulators controlling the cell cycle in human cells. Genome Res. 2003; 13(5):773-80. PMC: 430898. DOI: 10.1101/gr.947203. View

Oki S, Ohta T, Shioi G, Hatanaka H, Ogasawara O, Okuda Y . ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data. EMBO Rep. 2018; 19(12). PMC: 6280645. DOI: 10.15252/embr.201846255. View

Jayaram N, Usvyat D, Martin A . Evaluating tools for transcription factor binding site prediction. BMC Bioinformatics. 2016; 17(1):547. PMC: 6889335. DOI: 10.1186/s12859-016-1298-9. View

Zheng J, Wu J, Sun Z . An approach to identify over-represented cis-elements in related sequences. Nucleic Acids Res. 2003; 31(7):1995-2005. PMC: 152803. DOI: 10.1093/nar/gkg287. View

Niwa H . The principles that govern transcription factor network functions in stem cells. Development. 2018; 145(6). DOI: 10.1242/dev.157420. View

Frith M, Fu Y, Yu L, Chen J, Hansen U, Weng Z . Detection of functional DNA motifs via statistical over-representation. Nucleic Acids Res. 2004; 32(4):1372-81. PMC: 390287. DOI: 10.1093/nar/gkh299. View

10.

Takahashi K, Yamanaka S . A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol. 2016; 17(3):183-93. DOI: 10.1038/nrm.2016.8. View

11.

Cheneby J, Menetrier Z, Mestdagh M, Rosnet T, Douida A, Rhalloussi W . ReMap 2020: a database of regulatory regions from an integrative analysis of Human and Arabidopsis DNA-binding sequencing experiments. Nucleic Acids Res. 2019; 48(D1):D180-D188. PMC: 7145625. DOI: 10.1093/nar/gkz945. View

12.

Hughes J, Estep P, Tavazoie S, Church G . Computational identification of cis-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiae. J Mol Biol. 2000; 296(5):1205-14. DOI: 10.1006/jmbi.2000.3519. View

13.

Sharan R, Ovcharenko I, Ben-Hur A, Karp R . CREME: a framework for identifying cis-regulatory modules in human-mouse conserved segments. Bioinformatics. 2003; 19 Suppl 1:i283-91. DOI: 10.1093/bioinformatics/btg1039. View

14.

Ambrosini G, Groux R, Bucher P . PWMScan: a fast tool for scanning entire genomes with a position-specific weight matrix. Bioinformatics. 2018; 34(14):2483-2484. PMC: 6041753. DOI: 10.1093/bioinformatics/bty127. View

15.

Kim J, Cunningham R, James B, Wyder S, Gibson J, Niehuis O . Functional characterization of transcription factor motifs using cross-species comparison across large evolutionary distances. PLoS Comput Biol. 2010; 6(1):e1000652. PMC: 2813253. DOI: 10.1371/journal.pcbi.1000652. View

16.

Stormo G . DNA binding sites: representation and discovery. Bioinformatics. 2000; 16(1):16-23. DOI: 10.1093/bioinformatics/16.1.16. View

17.

Bailey T, Gribskov M . Combining evidence using p-values: application to sequence homology searches. Bioinformatics. 1998; 14(1):48-54. DOI: 10.1093/bioinformatics/14.1.48. View

18.

Fan A, Papadopoulos G, Hossain M, Lin I, Hu J, Tang T . Genomic and proteomic analysis of transcription factor TFII-I reveals insight into the response to cellular stress. Nucleic Acids Res. 2014; 42(12):7625-41. PMC: 4081084. DOI: 10.1093/nar/gku467. View

19.

Papatsenko D, Makeev V, Lifanov A, Regnier M, Nazina A, Desplan C . Extraction of functional binding sites from unique regulatory regions: the Drosophila early developmental enhancers. Genome Res. 2002; 12(3):470-81. PMC: 155290. DOI: 10.1101/gr.212502. View

20.

Kheradpour P, Stark A, Roy S, Kellis M . Reliable prediction of regulator targets using 12 Drosophila genomes. Genome Res. 2007; 17(12):1919-31. PMC: 2099599. DOI: 10.1101/gr.7090407. View