ConBind: Motif-aware Cross-species Alignment for the Identification of Functional Transcription Factor Binding Sites

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2016 Jan 2

PMID 26721389

Citations 5

Authors

Stefan H Lelieveld

Judith Schutte

Maurits J J Dijkstra

Punto Bawono

Sarah J Kinston

Berthold Gottgens

Jaap Heringa

Nicola Bonzanni

Affiliations

Soon will be listed here.

Abstract

Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well as distal enhancers. TFs recognize short, but specific binding sites (TFBSs) that are located within the promoter and enhancer regions. Functionally relevant TFBSs are often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) is a potent tool to detect the phylogenetic signal, the current MSA implementations are optimized to align the maximum number of identical nucleotides. This approach might result in the omission of conserved motifs that contain interchangeable nucleotides such as the ETS motif (IUPAC code: GGAW). Here, we introduce ConBind, a novel method to enhance alignment of short motifs, even if their mutual sequence similarity is only partial. ConBind improves the identification of conserved TFBSs by improving the alignment accuracy of TFBS families within orthologous DNA sequences. Functional validation of the Gfi1b + 13 enhancer reveals that ConBind identifies additional functionally important ETS binding sites that were missed by all other tested alignment tools. In addition to the analysis of known regulatory regions, our web tool is useful for the analysis of TFBSs on so far unknown DNA regions identified through ChIP-sequencing.

Citing Articles

The Dynamic Changes of Transcription Factors During the Development Processes of Human Biparental and Uniparental Embryos.

Zhang C, Li C, Yang L, Leng L, Jovic D, Wang J Front Cell Dev Biol. 2021; 9:709498.

PMID: 34604214 PMC: 8484909. DOI: 10.3389/fcell.2021.709498.

Refining pairwise sequence alignments of membrane proteins by the incorporation of anchors.

Staritzbichler R, Sarti E, Yaklich E, Aleksandrova A, Stamm M, Khafizov K PLoS One. 2021; 16(4):e0239881.

PMID: 33930031 PMC: 8087094. DOI: 10.1371/journal.pone.0239881.

Tailor-made multiple sequence alignments using the PRALINE 2 alignment toolkit.

Dijkstra M, van der Ploeg A, Feenstra K, Fokkink W, Abeln S, Heringa J Bioinformatics. 2019; 35(24):5315-5317.

PMID: 31368486 PMC: 6954659. DOI: 10.1093/bioinformatics/btz572.

Motif-Aware PRALINE: Improving the alignment of motif regions.

Dijkstra M, Bawono P, Abeln S, Feenstra K, Fokkink W, Heringa J PLoS Comput Biol. 2018; 14(11):e1006547.

PMID: 30383764 PMC: 6233922. DOI: 10.1371/journal.pcbi.1006547.

An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability.

Schutte J, Wang H, Antoniou S, Jarratt A, Wilson N, Riepsaame J Elife. 2016; 5:e11469.

PMID: 26901438 PMC: 4798972. DOI: 10.7554/eLife.11469.

References

Soldaini E, John S, Moro S, Bollenbacher J, Schindler U, Leonard W . DNA binding site selection of dimeric and tetrameric Stat5 proteins reveals a large repertoire of divergent tetrameric Stat5a binding sites. Mol Cell Biol. 1999; 20(1):389-401. PMC: 85094. DOI: 10.1128/MCB.20.1.389-401.2000. View

Bawono P, Heringa J . PRALINE: a versatile multiple sequence alignment toolkit. Methods Mol Biol. 2013; 1079:245-62. DOI: 10.1007/978-1-62703-646-7_16. View

Notredame C, Higgins D, Heringa J . T-Coffee: A novel method for fast and accurate multiple sequence alignment. J Mol Biol. 2000; 302(1):205-17. DOI: 10.1006/jmbi.2000.4042. View

Ikeda Y, Yamamoto J, Okamura M, Fujino T, Takahashi S, Takeuchi K . Transcriptional regulation of the murine acetyl-CoA synthetase 1 gene through multiple clustered binding sites for sterol regulatory element-binding proteins and a single neighboring site for Sp1. J Biol Chem. 2001; 276(36):34259-69. DOI: 10.1074/jbc.M103848200. View

Kent W, Sugnet C, Furey T, Roskin K, Pringle T, Zahler A . The human genome browser at UCSC. Genome Res. 2002; 12(6):996-1006. PMC: 186604. DOI: 10.1101/gr.229102. View

Gottgens B, Nastos A, Kinston S, Piltz S, Delabesse E, Stanley M . Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors. EMBO J. 2002; 21(12):3039-50. PMC: 126046. DOI: 10.1093/emboj/cdf286. View

Katoh K, Misawa K, Kuma K, Miyata T . MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 2002; 30(14):3059-66. PMC: 135756. DOI: 10.1093/nar/gkf436. View

Osawa M, Yamaguchi T, Nakamura Y, Kaneko S, Onodera M, Sawada K . Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis. Blood. 2002; 100(8):2769-77. DOI: 10.1182/blood-2002-01-0182. View

Chapman M, Charchar F, Kinston S, Bird C, Grafham D, Rogers J . Comparative and functional analyses of LYL1 loci establish marsupial sequences as a model for phylogenetic footprinting. Genomics. 2003; 81(3):249-59. DOI: 10.1016/s0888-7543(03)00005-3. View

10.

Gottgens B, Broccardo C, Sanchez M, Deveaux S, Murphy G, Gothert J . The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5' bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol. 2004; 24(5):1870-83. PMC: 350551. DOI: 10.1128/MCB.24.5.1870-1883.2004. View

11.

Edgar R . MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004; 32(5):1792-7. PMC: 390337. DOI: 10.1093/nar/gkh340. View

12.

Loots G, Ovcharenko I . rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucleic Acids Res. 2004; 32(Web Server issue):W217-21. PMC: 441521. DOI: 10.1093/nar/gkh383. View

13.

Sandelin A, Wasserman W, Lenhard B . ConSite: web-based prediction of regulatory elements using cross-species comparison. Nucleic Acids Res. 2004; 32(Web Server issue):W249-52. PMC: 441510. DOI: 10.1093/nar/gkh372. View

14.

Bacon D, Anderson W . Multiple sequence alignment. J Mol Biol. 1986; 191(2):153-61. DOI: 10.1016/0022-2836(86)90252-4. View

15.

Black W . The CE plane: a graphic representation of cost-effectiveness. Med Decis Making. 1990; 10(3):212-4. DOI: 10.1177/0272989X9001000308. View

16.

Meyers S, Downing J, Hiebert S . Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol. 1993; 13(10):6336-45. PMC: 364692. DOI: 10.1128/mcb.13.10.6336-6345.1993. View

17.

Thompson J, Higgins D, Gibson T . CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994; 22(22):4673-80. PMC: 308517. DOI: 10.1093/nar/22.22.4673. View

18.

Sharrocks A, Brown A, Ling Y, Yates P . The ETS-domain transcription factor family. Int J Biochem Cell Biol. 1998; 29(12):1371-87. DOI: 10.1016/s1357-2725(97)00086-1. View

19.

Thompson J, Plewniak F, Poch O . A comprehensive comparison of multiple sequence alignment programs. Nucleic Acids Res. 1999; 27(13):2682-90. PMC: 148477. DOI: 10.1093/nar/27.13.2682. View

20.

Heringa J . Two strategies for sequence comparison: profile-preprocessed and secondary structure-induced multiple alignment. Comput Chem. 1999; 23(3-4):341-64. DOI: 10.1016/s0097-8485(99)00012-1. View