Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet
Open accessPreprint — published as 10.1186/s13059-023-03070-0 · Paper page
Abstract
Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult. Here, we developed methods to identify transcription factor binding sites in modified DNA. Our models expand the standard A/C/G/T DNA alphabet to include cytosine modifications. We developed Cytomod to create modified genomic sequences and enhanced the Multiple EM for Motif Elicitation (MEME) Suite by adding the capacity to handle custom alphabets. We adapted the well-established position weight matrix (PWM) model of transcription factor binding affinity to this expanded DNA alphabet. Using these methods, we identified modification-sensitive transcription factor binding motifs. We confirmed established binding preferences, such as the preference of ZFP57 and C/EBPβ for methylated motifs and the preference of c-Myc for unmethylated E-box motifs. Using known binding preferences to tune model parameters, we discovered novel modified motifs for a wide array of transcription factors. Finally, we validated predicted binding preferences of OCT4 using cleavage under targets and release using nuclease (CUT&RUN) experiments across conventional, methylation-, and hydroxymethylation-enriched sequences. Our approach readily extends to other DNA modifications. As more genome-wide single-base resolution modification data becomes available, we expect that our method will yield insights into altered transcription factor binding affinities across many different modifications.
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- Authors
- Viner, C., Ishak, C. A., Johnson, J., Walker, N. J., Shi, H., Sjöberg-Herrera, M. K., Shen, S. Y., Lardo, S. M., Adams, D. J., Ferguson-Smith, A. C., De Carvalho, D. D., Hainer, S. J., Bailey, T. L., & Hoffman, M. M.
- Affiliations
- University Health Network (CA)
- The University of Queensland (AU)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- University of Pittsburgh (US)
- University of Nevada, Reno (US)
- Corresponding author
- Hoffman, Michael M.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2016-03-15
- OpenAlex
- W2299876992
- Cited by
- 18
- References
- 166
- Citations by year
- 2024: 2 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 6 · 2018: 2 · 2017: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Princess Margaret Cancer Foundation (MC-2015-16)
- Wellcome Trust (WT095606RR)
- Compute Canada
- Western Canada Research Grid
- Government of Ontario
- Agenția Națională pentru Cercetare și Dezvoltare
- Ontario Ministry of Research, Innovation and Science (ER-15-11-223)
- University of Toronto (MC-2015-16)
- China Scholarship Council
- Agencia Nacional de Investigación y Desarrollo (1171004)
- National Institutes of Health (2015-16)
- Canadian Institutes of Health Research (201512MSH-360970, 201512MSH‐)
- Natural Sciences and Engineering Research Council of Canada (rgpin-2015-03948, 03948, RGPIN-2015)
- Medical Research Council (MR/J001597/1, MR/J001597)
- Comisión Nacional de Investigación Científica y Tecnológica
- CHIST-ERA
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- transcription factor binding motifs, DNA methylation, cytosine modification, position weight matrices, ZFP57, C/EBPβ, c-Myc, Oct4, hydroxymethylation, binding affinity prediction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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