Luk, H. | Search bioRxiv

bioRxiv2020

Genes and Pathways for Plasma Lipid Traits via Multi-tissue Multi-omics Systems Analysis

Genome-wide association studies (GWAS) have implicated [~]380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides (TG), from GWAS were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in interferon signaling, autoimmune/immune activation, visual transduction, and protein catabolism were significantly associated with all lipid traits. Additionally, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL, glutathione metabolism for HDL, valine, leucine and isoleucine biosynthesis for TC, and insulin signaling and complement pathways for TG. Finally, utilizing gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g. APOH, APOA4, and ABCA1) and novel (e.g. F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36, reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.

systems biology↗

bioRxiv2018

Prenatal Bisphenol A Exposure in Mice Induces Multi-tissue Multi-omics Disruptions Linking to Cardiometabolic Disorders

The health impacts of endocrine disrupting chemicals (EDCs) remain debated and their tissue and molecular targets are poorly understood. Here we leveraged systems biology approaches to assess the target tissues, molecular pathways, and gene regulatory networks associated with prenatal exposure to the model EDC Bisphenol A (BPA). Prenatal BPA exposure led to scores of transcriptomic and methylomic alterations in the adipose, hypothalamus, and liver tissues in mouse offspring, with cross-tissue perturbations in lipid metabolism as well as tissue-specific alterations in histone subunits, glucose metabolism and extracellular matrix. Network modeling prioritized main molecular targets of BPA, including Pparg, Hnf4a, Esr1, and Fasn. Lastly, integrative analyses identified the association of BPA molecular signatures with cardiometabolic phenotypes in mouse and human. Our multi-tissue, multi-omics investigation provides strong evidence that BPA perturbs diverse molecular networks in central and peripheral tissues, and offers insights into the molecular targets that link BPA to human cardiometabolic disorders.\n\nAuthor summaryThe inability to pinpoint the mechanistic underpinnings of environmentally-induced diseases likely stems from the pleiotropic effects of chemicals such as BPA on diverse tissues and molecular space (transcriptome, epigenome, etc.). This makes it challenging to fully dissect their health impact and merits a call for modern big data approaches to examine environmental factors. Our data-driven study is the first unbiased, multi-tissue multiomic systems biology investigation of the molecular circuitry and mechanisms underlying offspring response to prenatal BPA exposure. Importantly, the incorporation of network-based modeling allows us to capture novel players in the regulation of BPA activities in vivo, and the integration with human disease association datasets helps bridge the molecular pathways affected by BPA with diverse human diseases. In doing so, our study provides compelling molecular evidence that developmental BPA exposure significantly perturbs metabolic and endocrine systems in the offspring, and supports BPA as one of the environmental factors involved in the developmental origins of health and disease (DOHaD).

systems biology↗