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bioRxiv · 10.1101/630756

A DNA recognition code for probing the in vivo functions of zinc finger transcription factors at domain resolution

Dogan, B.·Kailasam, S.·Corchado, A. H.·Najafabadi, H. S.
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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.

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Dogan, B., Kailasam, S., Corchado, A. H., Najafabadi, H. S.. 2019-05-07. A DNA recognition code for probing the in vivo functions of zinc finger transcription factors at domain resolution. https://doi.org/10.1101/630756

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