TY - JOUR
T1 - Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion
AU - Vitobello, Antonio
AU - Perner, Juliane
AU - Beil, Johanna
AU - Zhu, Jiang
AU - Del Río-Espínola, Alberto
AU - Morawiec, Laurent
AU - Westphal, Magdalena
AU - Dubost, Valérie
AU - Altorfer, Marc
AU - Naumann, Ulrike
AU - Mueller, Arne
AU - Kapur, Karen
AU - Borowsky, Mark
AU - Henderson, Colin
AU - Wolf, C. Roland
AU - Schwarz, Michael
AU - Moggs, Jonathan
AU - Terranova, Rémi
N1 - This work was supported by Innovative Medicine Initiative Joint Undertaking (115001) (MARCAR project: http://www.imi.marcar.eu/) and Novartis. C R Wolf was a recipient of a Cancer Research UK program grant C4639/A10822. J Perner, J Beil, J Zhu, A Del R´ıo-Esp´ınola, L Morawiec, M Westphal, V Dubost, M Altorfer, U Naumann, A Mueller, K Kapur, M Borowsky, J Moggs, and R Terranova are full time employees of Novartis. A Vitobello was a recipient of a Novartis Institutes for Biomedical Research Postdoctoral Fellowships.
© 2019 Vitobello et al.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85073440663&partnerID=8YFLogxK
U2 - 10.26508/lsa.201900461
DO - 10.26508/lsa.201900461
M3 - Article
C2 - 31615920
SN - 2575-1077
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
IS - 5
M1 - e201900461
ER -
