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Discovering Motifs in Ranked Lists of DNA Sequences
Open accessAbstract
Computational methods for discovery of sequence elements that are enriched in a target set compared with a background set are fundamental in molecular biology research. One example is the discovery of transcription factor binding motifs that are inferred from ChIP-chip (chromatin immuno-precipitation on a microarray) measurements. Several major challenges in sequence motif discovery still require consideration: (i) the need for a principled approach to partitioning the data into target and background sets; (ii) the lack of rigorous models and of an exact p-value for measuring motif enrichment; (iii) the need for an appropriate framework for accounting for motif multiplicity; (iv) the tendency, in many of the existing methods, to report presumably significant motifs even when applied to randomly generated data. In this paper we present a statistical framework for discovering enriched sequence elements in ranked lists that resolves these four issues. We demonstrate the implementation of this framework in a software application, termed DRIM (discovery of rank imbalanced motifs), which identifies sequence motifs in lists of ranked DNA sequences. We applied DRIM to ChIP-chip and CpG methylation data and obtained the following results. (i) Identification of 50 novel putative transcription factor (TF) binding sites in yeast ChIP-chip data. The biological function of some of them was further investigated to gain new insights on transcription regulation networks in yeast. For example, our discoveries enable the elucidation of the network of the TF ARO80. Another finding concerns a systematic TF binding enhancement to sequences containing CA repeats. (ii) Discovery of novel motifs in human cancer CpG methylation data. Remarkably, most of these motifs are similar to DNA sequence elements bound by the Polycomb complex that promotes histone methylation. Our findings thus support a model in which histone methylation and CpG methylation are mechanistically linked. Overall, we demonstrate that the statistical framework embodied in the DRIM software tool is highly effective for identifying regulatory sequence elements in a variety of applications ranging from expression and ChIP-chip to CpG methylation data. DRIM is publicly available at http://bioinfo.cs.technion.ac.il/drim.
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“These were enriched for specialized programs across ages: Embryonic epithelia upregulated genes for developmental processes (Figure 3K, S3K), while aged epithelia upregulated host-defense programs (Figure 3L, FDR q-value < 0.01, GOrilla (Eden et al., 2007, 2009;Baruch et al., 2014).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Eden et al., 2007
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Metadata
- Authors
- Eden, E., Lipson, D., Yogev, S., & Yakhini, Z.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Eden, Eran
- ORCID
- Lipson, Doron
- Venue
- PLoS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2007-03-23
- Volume
- 3
- Issue
- 3
- Pages
- e39
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC1829477
- OpenAlex
- W1981093360
- Cited by
- 696
- References
- 65
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 23 · 2023: 44 · 2022: 42 · 2021: 80 · 2020: 54 · 2019: 57 · 2018: 53 · 2017: 52 · 2016: 53 · 2015: 36 · 2014: 31 · 2013: 41 · 2012: 22
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Hebrew University of Jerusalem
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- motif discovery, ranked lists, transcription factor binding sites, ChIP-chip, CpG methylation, motif enrichment, Polycomb complexes, histone methylation, CA repeats
- MeSH terms
- Algorithms, Base Sequence, Molecular Sequence Data, Regulatory Sequences, Nucleic Acid, Sequence Homology, Nucleic Acid, Software, Sequence Alignment, Conserved Sequence, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Chromatin Immunoprecipitation
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