Degron Protease Blockade Sensor to Image Epigenetic
Histone Protein Methylation in Cells and Living Animals
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Abstract
Lysine
methylation of histone H3 and H4 has been identified as
a promising therapeutic target in treating various cellular diseases.
The availability of an <i>in vivo</i> assay that enables
rapid screening and preclinical evaluation of drugs that potentially
target this cellular process will significantly expedite the pace
of drug development. This study is the first to report the development
of a real-time molecular imaging biosensor (a fusion protein, [FLuc2]-[Suv39h1]-[(G4S)<sub>3</sub>]-[H3-K9]-[cODC]) that can detect and monitor the methylation
status of a specific histone lysine methylation mark (H3-K9) in live
animals. The sensitivity of this sensor was assessed in various cell
lines, in response to down-regulation of methyltransferase EHMT2 by
specific siRNA, and in nude mice with lysine replacement mutants. <i>In vivo</i> imaging in response to a combination of methyltransferase
inhibitors BIX01294 and Chaetocin in mice reveals the potential of
this sensor for preclinical drug evaluation. This biosensor thus has
demonstrated its utility in the detection of H3-K9 methylations <i>in vivo</i> and potential value in preclinical drug development