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A domain-resolution map of in vivo DNA binding reveals the regulatory consequences of somatic mutations in zinc finger transcription factors

Berat Dogan, View ORCID ProfileSenthilkumar Kailasam, Aldo Hernández Corchado, Naghmeh Nikpoor, View ORCID ProfileHamed S. Najafabadi
doi: https://doi.org/10.1101/630756
Berat Dogan
1Department of Human Genetics, McGill University, Montreal, QC, Canada
2McGill Genome Centre, Montreal, QC, Canada
4Department of Biomedical Engineering, Inonu University, Malatya, Turkey
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Senthilkumar Kailasam
1Department of Human Genetics, McGill University, Montreal, QC, Canada
2McGill Genome Centre, Montreal, QC, Canada
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Aldo Hernández Corchado
1Department of Human Genetics, McGill University, Montreal, QC, Canada
2McGill Genome Centre, Montreal, QC, Canada
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Naghmeh Nikpoor
3Rosell Institute for Microbiome and Probiotics, Montreal, QC, Canada
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Hamed S. Najafabadi
1Department of Human Genetics, McGill University, Montreal, QC, Canada
2McGill Genome Centre, Montreal, QC, Canada
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  • ORCID record for Hamed S. Najafabadi
  • For correspondence: hamed.najafabadi@mcgill.ca
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ABSTRACT

Multi-zinc finger proteins constitute the largest class of human transcription factors. Their DNA-binding specificity is usually encoded by a subset of their tandem Cys2His2 zinc finger (ZF) domains – the subset that binds to DNA, however, is often unknown. Here, by combining a context-aware machine-learning-based model of DNA recognition with in vivo binding data, we characterize the sequence preferences and the ZF subset that is responsible for DNA binding in 209 human multi-ZF proteins. We show that in vivo DNA binding is primarily driven by ∼50% of the ZFs – these DNA-binding ZFs are under strong selective pressure within and across species, and their mutations affect the expression of hundreds of genes as revealed by pan-cancer trans-eQTL analysis across 18 tissues. Among the genes affected by mutations in multi-ZF proteins, we identify several oncogenic factors regulated by SP1, and show that SP1 up-regulation in cancer promotes the expression of these genes while mutations in SP1 ZFs lead to their repression. Together, these analyses suggest that mutations in DNA-binding ZFs have distinct and widespread regulatory consequences that contribute to transcriptome remodelling in cancer.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 16, 2020.
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A domain-resolution map of in vivo DNA binding reveals the regulatory consequences of somatic mutations in zinc finger transcription factors
Berat Dogan, Senthilkumar Kailasam, Aldo Hernández Corchado, Naghmeh Nikpoor, Hamed S. Najafabadi
bioRxiv 630756; doi: https://doi.org/10.1101/630756
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A domain-resolution map of in vivo DNA binding reveals the regulatory consequences of somatic mutations in zinc finger transcription factors
Berat Dogan, Senthilkumar Kailasam, Aldo Hernández Corchado, Naghmeh Nikpoor, Hamed S. Najafabadi
bioRxiv 630756; doi: https://doi.org/10.1101/630756

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