*EASTBIO* Structural and functional studies of WIZ, a zinc-finger protein required in epigenetic regulation of gene expression

Background: The G9a/GLP complex of lysine methylases plays a critical role in epigenetic regulation of gene expression, maintenance of genomic imprinting and spatial organization of chromatin in the nucleus of mammalian cells. Genetic loss of complex components leads to embryonic lethality and heterozygosity is associated with developmental delay and intellectual disability. The widely interspersed zinc-finger protein WIZ is a stable component of the G9a/GLP complex, but its function is not well understood. Our recent work has shown that WIZ interacts with double-stranded DNA in a sequence-specific manner and without sequence specificity, but with higher affinity, with single-stranded DNA and RNA.

Aims: The project aims to investigate, in detail, the interaction of WIZ with nucleic acids and the role of these interactions in epigenetic regulation of gene expression in mammalian cells.

Experimental work: Biochemical, biophysical and synthetic biology approaches will be applied to characterize the affinity of recombinant WIZ zinc fingers to different types of nucleic acids. The structure of WIZ bound to nucleic acids (RNA and DNA) will be solved by either protein X-ray crystallography or alternative methods. In parallel, the interaction of WIZ with the catalytic core of G9a/GLP will be investigated using structural biology approaches. These experiments will be complemented with functional characterisation of specific mutations introduced into the endogenous WIZ by CRISPR/Cas9-mediated gene editing in embryonic stem cells.

Lab web site url: http://stancheva.bio.ed.ac.uk

Lab web site url: http://cook.bio.ed.ac.uk