Histone H3 lysine 4 methylation signature associated with human undernutrition

TLDR

Stunting in children under two in urban slums arises from poor nutrition, infections, and parental factors, yet the epigenetic consequences of such environments remain largely unexplored. This study aimed to chart the temporal dynamics of histone H3 lysine 4 trimethylation (H3K4me3) in children and their mothers living in a Dhaka slum. Using longitudinal chromatin immunoprecipitation sequencing of blood cells, the authors profiled H3K4me3 across developmental stages, compared it to H3K27ac, and integrated methylation redistribution with transcriptomic networks to assess nutrient‑related epigenetic changes. They found a progressive loss of H3K4me3 at promoter regions and gain at ectopic sites in stunted children, a pattern linked to metabolic and immune genes, mirroring in‑vitro one‑carbon deficiency effects, and identified reduced LDL receptor 1 expression as a driver of stunting that may serve as an intervention target.

Abstract

Chronically undernourished children become stunted during their first 2 years and thereafter bear burdens of ill health for the rest of their lives. Contributors to stunting include poor nutrition and exposure to pathogens, and parental history may also play a role. However, the epigenetic impact of a poor environment on young children is largely unknown. Here we show the unfolding pattern of histone H3 lysine 4 trimethylation (H3K4me3) in children and mothers living in an urban slum in Dhaka, Bangladesh. A pattern of chromatin modification in blood cells of stunted children emerges over time and involves a global decrease in methylation at canonical locations near gene start sites and increased methylation at ectopic sites throughout the genome. This redistribution occurs at metabolic and immune genes and was specific for H3K4me3, as it was not observed for histone H3 lysine 27 acetylation in the same samples. Methylation changes in stunting globally resemble changes that occur in vitro in response to altered methylation capacity, suggesting that reduced levels of one-carbon nutrients in the diet play a key role in stunting in this population. A network of differentially expressed genes in stunted children reveals effects on chromatin modification machinery, including turnover of H3K4me3, as well as posttranscriptional gene regulation affecting immune response pathways and lipid metabolism. Consistent with these changes, reduced expression of the endocytic receptor gene LDL receptor 1 (LRP1) is a driver of stunting in a mouse model, suggesting a target for intervention.