Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

Authors: WULFRIDGE, PHILLIP - Johns Hopkins University School Of Medicine; DAVIDOVICH, ADAM - Johns Hopkins University School Of Medicine; SALVADOR, ANNA - Texas A&M University; MANNO, GABRIELLE - Texas A&M University; TRYGGVADOTTIR, RAKEL - Johns Hopkins University School Of Medicine; IDRIZI, ADRIAN - Johns Hopkins University School Of Medicine; HUDA, NAZMUL - University Of California, Davis; Bennett, Brian; ADAMS, L. GARRY - Texas A&M University; HANSEN, KASPER - Johns Hopkins University School Of Medicine; THREADGILL, DAVID - Texas A&M University; FEINBERG, ANDREW - Johns Hopkins University School Of Medicine

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/25/2023
Publication Date: 10/23/2023
Citation: Wulfridge, P., Davidovich, A., Salvador, A.C., Manno, G., Tryggvadottir, R., Idrizi, A., Huda, N., Bennett, B.J., Adams, L., Hansen, K.D., Threadgill, D.W., Feinberg, A.P. 2023. Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1010997.
DOI: https://doi.org/10.1371/journal.pgen.1010997

Interpretive Summary: Personalized medicine, the configuration of therapeutic regimens on an individual basis, is critical for addressing public health issues, especially those related to environmental exposure. The importance of genotype and the epigenome in mediating phenotypic responses to environmental factors, and the overwhelming diversity of individual responses compared to population-level measurements, has become increasingly clear in recent years. Here we follow a new experimental paradigm in which we identify GxD changes in DNA methylation and gene expression in a cohort of genetically diverse mouse strains, apply the pathway analysis from those studies to inform a literature-based selection of a predicted strain-specific drug intervention, and assess the molecular and phenotypic consequences of this intervention in a strain-specific manner). Specifically, we identified as a candidate genotype-specific therapy a Farnesoid X Receptor (FXR) agonist based on the observation of strain-specific modulation of the FXR pathway, and found that this drug not only has beneficial effects on the strain predicted to be responsive, but also shows strain-specific adverse responses in the strain predicted to be insensitive. In so doing, we have identified an example of both strain-specific disease phenotype mitigation and strain-specific deleterious side effects.

Technical Abstract: Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic integration is complicated by the lack of environmental or genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, BL6, A/J, and NOD, to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed comprehensive genomic DNA methylation and transcriptomic analysis, and found overlapping but also highly divergent changes in DNA methylation and gene expression upstream of the diversity of metabolic phenotypes. Strain-specific pathway analysis of dietary effects reveals a dysregulation of cholesterol biosynthesis common to all three strains, but a divergence in the upstream regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators. As a pilot study, we administered GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts genotype-specific protection against dietary effects in BL6 as predicted by our epigenetic analysis, as well as increased inflammatory-related side effects in NOD. This pilot study demonstrates the potential efficacy of precision therapy for genotype-informed dietary metabolic intervention, and a mouse platform for guiding this approach.