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Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion

vitobello, Antonio and Perner, Juliane and Beil, Johanna and Zhu, Jiang and Del Rio Espinola, Alberto and Morawiec, Laurent and Westphal, Magdalena and Dubost, Valerie and Altorfer, Marc and Naumann, Ulrike and Mueller, Arne and Kapur, Karen and Borowsky, Mark and Henderson, Colin and Wolf, Roland and Schwarz, Michael and Moggs, Jonathan and Terranova, Remi (2019) Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion. Life Science Alliance.

Abstract

Liver cancer susceptibility varies amongst humans and between experimental animal
models due to multiple genetic and epigenetic factors. The molecular characterization of
such susceptibilities has the potential to enhance cancer risk assessment of xenobiotic
exposures and disease prevention strategies. Here, using DNase I hypersensitivity
mapping coupled with transcriptomic profiling, we investigate perturbations in cis-acting
gene regulatory elements associated with the early stages of phenobarbital (PB)-
mediated liver tumor promotion in susceptible versus resistant mouse strains (B6C3F1
versus C57BL/6J). Integrated computational analyses of strain-selective changes in
liver chromatin accessibility underlying PB-response reveal differential epigenetic
regulation of molecular pathways associated with PB-mediated tumor promotion,
including Wnt/-catenin signalling. Complementary transcription factor motif analyses
reveal mouse strain-selective gene regulatory networks and a novel role for Stat, Smad
and Fox transcription factors in the early stages of PB-mediated tumor promotion.
Mapping perturbations in cis-acting gene regulatory elements provides novel insights
into the molecular basis for susceptibility to xenobiotic-induced rodent liver tumor
promotion and has the potential to enhance mechanism-based cancer risk assessments
of xenobiotic exposures.

Item Type: Article
Keywords: Liver tumor promotion, Phenobarbital (PB), Enhancers, Open chromatin landscape, Transcription factors
Date Deposited: 11 Dec 2019 00:45
Last Modified: 11 Dec 2019 00:45
URI: https://oak.novartis.com/id/eprint/39727

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