RT Journal Article
SR Electronic
T1 Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900461
DO 10.26508/lsa.201900461
VO 2
IS 5
A1 Vitobello, Antonio
A1 Perner, Juliane
A1 Beil, Johanna
A1 Zhu, Jiang
A1 Del Río-Espínola, Alberto
A1 Morawiec, Laurent
A1 Westphal, Magdalena
A1 Dubost, Valérie
A1 Altorfer, Marc
A1 Naumann, Ulrike
A1 Mueller, Arne
A1 Kapur, Karen
A1 Borowsky, Mark
A1 Henderson, Colin
A1 Wolf, C Roland
A1 Schwarz, Michael
A1 Moggs, Jonathan
A1 Terranova, Rémi
YR 2019
UL https://www.life-science-alliance.org/content/2/5/e201900461.abstract
AB Liver cancer susceptibility varies amongst humans and between experimental animal models because of 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/β-catenin signaling. 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.