On the prediction of DNA-binding preferences of C2H2-ZF domains using structural models: application on human CTCF

Abstract

Cis2-His2 zinc finger (C2H2-ZF) proteins are the largest family of transcription factors in human and higher metazoans. To date, the DNA-binding preferences of many members of this family remain unknown. We have developed a computational method to predict their DNA-binding preferences. We have computed theoretical position weight matrices (PWMs) of proteins composed by C2H2-ZF domains, with the only requirement of an input structure. We have predicted more than two-third of a single zinc-finger domain binding site for about 70% variants of Zif268, a classical member of this family. We have successfully matched between 60 and 90% of the binding-site motif of examples of proteins composed by three C2H2-ZF domains in JASPAR, a standard database of PWMs. The tests are used as a proof of the capacity to scan a DNA fragment and find the potential binding sites of transcription-factors formed by C2H2-ZF domains. As an example, we have tested the approach to predict the DNA-binding preferences of the human chromatin binding factor CTCF. We offer a server to model the structure of a zinc-finger protein and predict its PWM.

Spanish Ministry of Economy (MICINN) [BIO2017-85329-R, RYC2015-17519, MDM2014-0370] and European Regional Development Fund (FEDER) [BIO2017-85329-R, RYC-2015-17519, MDM-2014-0370]; Erasmus+ Fellowship 2019 by EU (to F.Å.); Research Formation of ‘Generalitat de Catalunya’ (FI) Fellowship (to A.M).