Rational Design of Artificial Genetic Switches
To produce a genetic switch that turns on specific gene expression, we developed a
histone deacetylase (HDAC) inhibitor conjugated to pyrrole–imidazole polyamide (PIP)
that has remarkable properties such as sequence-specific DNA binding, effects on cell
permeability, and nuclear localization. We constructed a library of 32 types of PIP
conjugates that bind to different base sequences and has evaluated gene expression
using DNA microarray technology in mice and human cells. We demonstrated that upregulation
of gene expression in different transcriptional networks is based on
sequence specificity.1 To develop a genetic switch that turns off specific gene
expression, we synthesized a functional PIP with a DNA alkylating agent. Our research
group found that the functional polyamide targets the mutant (GTT) sequence of Kras
codon 12, which is found in colorectal cancer and pancreatic cancer where it effectively
suppresses Kras expression.2 We confirmed the compound’s effectiveness in
experiments using human colorectal cancer cells and tumor-bearing mice. We have
also developed functional polyamides that inhibit the binding of RUNX family genes,
which are among the key transcription factors responsible for tumor growth and are
drug candidates for the treatment of leukemia, lung cancer, and stomach cancer.3
Therefore, strategies to expand our tunable PIPs could create an epoch-making
approach to modulate the desired gene expressions. Recently, we installed cooperative
binding host-guest unit to PIP and demonstrated potent cooperative inhibitory effects
on gene expression under physiological conditions by disrupting transcription factors-
DNA binding.4 In this talk recent progress of regulation of the gene expression using
designed PIPs will be discussed.
Date: 29 June 2018, 11:00 (Friday, 10th week, Trinity 2018)
Venue: NDM Building, Headington OX3 7FZ
Venue Details: Basement seminar room, TDI
Speaker: Professor Hiroshi Sugiyama (Kyoto University)
Organising department: Ludwig Institute for Cancer Research, Oxford Branch
Organiser: Christina Woodward (Oxford Ludwig Institute, Nuffield Department of Medicine, University of Oxford)
Organiser contact email address: christina.woodward@ludwig.ox.ac.uk
Host: Dr Skirmantas Kriaucionis (Ludwig Cancer Research)
Part of: Ludwig Institute Seminar Series
Booking required?: Not required
Audience: Members of the University only
Editor: Christina Woodward