Multi-omics Analysis of Umbilical Cord Hematopoietic Stem Cells from a Multi-ethnic Cohort of Hawaii Reveals the Intergenerational Effect of Maternal Pre-Pregnancy Obesity and Risk Prediction for Cancers

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). Differential methylation (DM) analysis unveiled a global hypermethylation pattern in the maternal pre-pregnancy obese group (BH adjusted p<0.05), adjusting for major clinical confounders. Functional analysis revealed significant associations of differentially methylated sites with downregulated cell cycle, lipid synthesis, immune signaling, and metabolic pathways. Utilizing Shannon entropy to evaluate uHSCs methylation levels, we discerned a notable impact of maternal obesity on higher quiescence of uHSCs. Further, the multi-omics integration revealed dysfunction in adipogenesis, erythropoietin production, cell differentiation and DNA repair. This study reveals a significant correlation between pre-pregnancy maternal obesity and multi-omics level molecular changes in the uHSCs of offspring, particularly in DNA methylation. These findings suggest that maternal obesity can lead to alterations that affect physiological pathways in the offspring. Overall design: Baby cord blood samples from 72 pregnant women (34 obese; 38 non-obese) who delivered at Kapiolani Medical Center for Women and Children in Honolulu, Hawaii (2016-2018) were collected. CD34+/CD38-/Lin- umbilical cord blood hematopoietic stem cells (uHSCs) were collected from cord blood for DNA methylation assay with Infinium HumanMethylation450. A total of 47 matching RNA samples were used for RNA sequencing.