Differential expression of genes influencing mitotic processes in cord blood mononuclear cells after a pre-conceptional micronutrient-based randomized controlled trial: Pune Rural Intervention in Young Adolescents (PRIYA)

Abstract

In the Pune Maternal Nutrition Study, low maternal vitamin B12 and high folate concentrations during pregnancy predicted adiposity and insulin resistance (diabesity) in the children. Based on these findings, we designed an RCT (PRIYA) to provide these nutrients pre-conceptionally to reduce diabesity in the offspring. The interventions included: 1) vitamin B12+multi-micronutrients and protein supplement (B12+MMN), 2) vitamin B12 alone, and 3) placebo. A total of 149 women became pregnant and delivered in the trial. We report results of RNA sequencing in the cord-blood mononuclear cells in 88 deliveries. Gene expression analysis revealed 20 differentially expressed genes (FDR <0.1, a discovery threshold) between the B12+MMN and placebo groups. The enriched biological processes included: chromosome segregation, nuclear division and organelle fission. A cell cycle checkpoint gene Claspin (CLSPN) was expressed less in the B12+MMN group but proliferation markers did not differ. No difference was observed between the B12 alone and placebo groups. The B-complex vitamins are essential for nucleotide synthesis and generation of S-Adenosyl Methionine, a universal cellular methyl donor and thereby may contribute to the regulation of gene expression. Vitamins A and D, and zinc in MMN may also influence gene expression. We propose that the multi-micronutrient intervention influenced rate of progression of specific phases of cell cycle without affecting proliferation. Vitamin B12 alone was not sufficient. We highlight a novel molecular mechanism for the effect of multi-micronutrients during fetal development, and a plausible mechanism for intergenerational nutritional programming. Follow up studies will help understand their implications on the future phenotype.