Work

Allele‐Specific Inhibition of Histone Demethylases

Year: 2019

Type: article

Abstract: Histone demethylases play a critical role in mammalian gene expression by removing methyl groups from lysine residues in degree- and site-specific manner. To specifically interrogate members and isoforms of this class of enzymes, we have developed demethylase variants with an expanded active site. The mutant enzymes are capable of performing lysine demethylation with wild-type proficiency, but are sensitive to inhibition by cofactor-competitive molecules embellished with a complementary steric "bump". The selected inhibitors show more than 20-fold selectivity over the wild-type demethylase, thus overcoming issues typical to pharmacological and genetic approaches. The mutant-inhibitor pairs are shown to act on a physiologically relevant full-length substrate. By engineering a conserved amino acid to achieve member-specific perturbation, this study provides a general approach for studying histone demethylases in diverse cellular processes.

Source: ChemBioChem

DOI: 10.1002/cbic.201800756

Authors: Shana Wagner, Megan Waldman, Simran Arora, Sinan Wang, Valerie Scott, Kabirul Islam

Institution: University of Pittsburgh

Language: English

Topic: Epigenetics and DNA Methylation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: University of Pittsburgh, National Institutes of Health, Directorate for Biological Sciences, National Institute of General Medical Sciences

Awards: G5642132304, Site-Specific Photochemistry on Epigenetic Readers for Interactome Profiling