PT  - JOURNAL ARTICLE
AU  - Dogan, Berat
AU  - Kailasam, Senthilkumar
AU  - Corchado, Aldo Hernández
AU  - Nikpoor, Naghmeh
AU  - Najafabadi, Hamed S.
TI  - A domain-resolution map of <em>in vivo</em> DNA binding reveals the regulatory consequences of somatic mutations in zinc finger transcription factors
AID  - 10.1101/630756
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 630756
4099  - http://biorxiv.org/content/early/2020/06/16/630756.short
4100  - http://biorxiv.org/content/early/2020/06/16/630756.full
AB  - 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 StatementThe authors have declared no competing interest.