From: Gregor Mendel Institute of Molecular Plant Biology, Vienna, Austria

Will give a seminar entitled:

Single residue changes in oncohistone core have the potential to cause neofunctionalization and impose fitness trade-offs relevant to disease

Histones are among the most conserved proteins in the eukaryotic genome, and their function is thought to be largely invariant. However, thousands oncohistone mutations are associated with various cancers and most remain uncharacterized. To provide an experimental approach whereby gain-of-function, emergent effects of such mutants can be identified and dissected, we examined over a billion years of the essential histone H2A.Z’s evolution in a single synthetic host. We identify single residue substitutions within the H2A.Z core domain loop 2 (L2) that led to the emergence of new H2A.Z variants. Such neomorphs are distinct by their ability to interact with the transcription apparatus, rewiring gene expression genome-wide by tuning transcription processivity, and directly imposing both adaptive opportunities and costs. Our results reveal that even changes of single residues within the histones core domain can transform their function, catalysing the rapid emergence of phenotypic diversity. Our synthetic mode of investigation provides a framework to understand the mechanistic underpinnings of disease-associated histone mutations. 

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