CSB Deptl Seminar: Prof. Tim Hughes, Dept of Medical Genetics & Microbiology, University of Toronto

CSB Departmental Seminar

Prof. Tim Hughes
Dept of Medical Genetics & Microbiology
University of Toronto

“Kaleidoscopic Evolution of C2H2 Zinc Finger Proteins”

Host: Prof. Maurice Ringuette

Refreshments will be served. All are welcome!

Video Conferencing at UTM (DV 4001) & UTSc (MW 229)

Abstract:
The C2H2 zinc finger (C2H2-ZF) is found in across the eukaryotes, and is the most numerous protein domain in many metazoans, representing nearly half of all human transcription factors. It is also one of the few protein domains that display widespread diversification, such that a majority of the ~700 human C2H2 proteins are expected to have unique binding motifs. Most C2H2 proteins, however, are largely unstudied in terms of both function and biochemistry, and it is unclear whether they even bind DNA and regulate transcription.

I will describe efforts in my lab to systematically characterize C2H2 proteins in human and across eukaryotes. We find that most C2H2 domains and most C2H2 proteins do bind DNA in a sequence specific manner. Rapid diversification of binding motifs in metazoans is facilitated by contribution of non-DNA-contacting residues to binding affinity, relative to non-metazoan C2H2 domains, enabling virtually unlimited combinations of DNA contacting residues, and continuous “kaleidoscopic” evolution over relatively short evolutionary timescales. We introduce new methods to integrate the identity of DNA contact residue identities with other residues and ChIP-seq data to improve both “recognition code” models and derivation of motifs from ChIP-seq. We observe widespread binding of C2H2 proteins to endogenous retroelements, providing a mechanism driving expansion and diversification. Surprisingly, we also find that the spectrum of C2H2 protein-protein interactions in living cells is nearly as diverse as the C2H2 DNA binding sites, suggesting that diversification involves multiple molecular mechanisms.