Abstract

Background Maternal obesity is a health concern that may predispose newborns to a high risk of medical problems later in life. To understand the transgenerational effect of maternal obesity, we conducted a multi-omics study, using DNA methylation and gene expression in the CD34+/CD38-/Lin-umbilical cord blood hematopoietic stem cells (uHSCs) and metabolomics of the cord blood, all from a multi-ethnic cohort (n=72) from Kapiolani Medical Center for Women and Children in Honolulu, Hawaii (collected between 2016 and 2018).

Results Differential methylation (DM) analysis unveiled a global hypermethylation pattern in the maternal pre-pregnancy obese group (BH adjusted p<0.05), after adjusting for major clinical confounders. Comprehensive functional analysis showed hypermethylation in promoters of genes involved in cell cycle, protein synthesis, immune signaling, and lipid metabolism. Utilizing Shannon entropy on uHSCs methylation, we discerned notably higher quiescence of uHSCs impacted by maternal obesity. Additionally, the integration of multi-omics data-including methylation, gene expression, and metabolomics-provided further evidence of dysfunctions in adipogenesis, erythropoietin production, cell differentiation, and DNA repair, aligning with the findings at the epigenetic level.

Conclusions This study reveals the significant correlation between pre-pregnancy maternal obesity and multi-omics level molecular changes in the uHSCs of offspring, particularly in DNA methylation.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This research was supported by grants R01 LM012373 and LM012907 awarded by NLM, and R01 HD084633 awarded by NICHD to L.X. Garmire, as well as in part by the NCI Cancer Center Support Grant (CCSG) number P30 CA071789 awarded to Genomics and Bioinformatics Shared Resource (RRID:SCR_019085). This research was supported in part by training funding provided by the NIH grant T32 GM141746 and Advanced Proteogenomics of Cancer (T32 CA140044).

Author Declarations

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Western IRB of the University of Hawaii gave ethical approval for this work (WIRB Protocol #20151223). All participants involved in this study provided written informed consent before the collection of cord blood samples.

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Data Availability

All data produced in the present work are contained in the manuscript

AbbreviationBHBenjamini-HochbergBMIBody mass indexCAcylcarnitinesDEDifferential expressionDIABLOData Integration Analysis for Biomarker discovery using Latent cOmponentsDMDifferential methylationDMRDifferentially methylated regionsDOHaDDevelopmental Origins of Health and DiseaseEWASEpigenome-wide association studiesFCFold ChangeFDRFalse positive resultsKEGGKyoto Encyclopedia of Genes and GenomesLASSOLeast absolute shrinkage and selection operatorLDALinear Discriminant AnalysisLOGLogistic regressionPAMPartition Around MedoidsPANDAPreferential Attachment-based common Neighbor Distribution derived AssociationsPC aaDiacyl phosphatidylcholinesPC aeAcyl-alkylphosphatidylcholinesPCCPearson correlation coefficientsPPIProtein-Protein InteractionRBFRadial Basis FunctionRFRandom ForestRPARTRecursive Partitioning and Regression TreesSOVSource of varianceSVDSingular value decompositionSVMSupportive Vector MachineTSSTranscription start siteuHSCsUmbilical cord blood hematopoietic stem cellsUMAPUniform Manifold Approximation and ProjectionVLCADVery long-chain acyl-CoA dehydrogenaseWGCNAWeighted Gene Co-expression Network Analysis