Multi-omics Analysis of Umbilical Cord Hematopoietic Stem Cells from a Multi-ethnic Cohort of Hawaii Reveals the Transgenerational Effect of Maternal Pre-Pregnancy Obesity

BackgroundMaternal obesity is a health concern that may predispose newborns to a high risk of medical problems later in life. To understand the intergenerational effect of maternal obesity, we hypothesized that the maternal obesity effect is mediated by epigenetic changes in the CD34+/CD38-/Lin- hematopoietic stem cells (uHSCs) in the offspring. Towards this, we conducted a DNA methylation centric multi-omics study. We measured the DNA methylation and gene expression in the CD34+/CD38-/Lin- 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). ResultsDifferential 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. KEGG pathway enrichment, WGCNA, and PPI analyses revealed hypermethylated CpG sites were involved in critical biological processes, including 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. Furthermore, we trained a random forest classifier using the CpG sites in the genes of the top pathways associated with maternal obesity, and applied it to predict cancer vs. adjacent normal labels from samples in 14 Cancer Genome Atlas (TCGA) cancer types. Five of 14 cancers showed balanced accuracy of 0.6 or higher: LUSC (0.87), PAAD (0.83), KIRC (0.71), KIRP (0.63) and BRCA (0.60). ConclusionsThis study revealed the significant correlation between pre-pregnancy maternal obesity and multi-omics level molecular changes in the uHSCs of offspring, particularly in DNA methylation. Moreover, these maternal obesity epigenetic markers in uHSCs may predispose offspring to higher risks in certain cancers.