A domain-resolution map ofin vivoDNA binding reveals the regulatory consequences of somatic mutations in zinc finger transcription factors
| Autor: | Naghmeh Nikpoor, Aldo H. Corchado, Senthilkumar Kailasam, Berat Dogan, Hamed S. Najafabadi |
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| Rok vydání: | 2019 |
| Předmět: |
Zinc finger
Genetics 0303 health sciences Somatic cell Biology 3. Good health Transcriptome 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry In vivo Psychological repression Transcription factor Gene 030217 neurology & neurosurgery DNA 030304 developmental biology |
| DOI: | 10.1101/630756 |
| Popis: | 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 within vivobinding data, we characterize the sequence preferences and the ZF subset that is responsible for DNA binding in 209 human multi-ZF proteins. We show thatin vivoDNA 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. |
| Databáze: | OpenAIRE |
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