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DNA Methylation Changes Uncovered in Undernourished Children

NEW YORK (GenomeWeb) – Children who are undernourished exhibit global changes in genomic methylation, according to a new study.

About a quarter of children worldwide have poor health due to nutrient insufficiency, and undernourishment causes about one-third of deaths among children under the age of five. Even among the children who survive, undernourishment leads to persistent health problems including stunting, vaccine failure, and cognitive impairments.

An international team of researchers led by investigators at the University of Virginia examined methylation patterns among children living in a slum in Dhaka, Bangladesh. As they reported in the Proceedings of the National Academy of Sciences today, the researchers found a pattern of histone H3 lysine 4 methylation rearrangements among stunted children that emerged over time that appeared to affect immune response and lipid metabolism pathways.

"It has been estimated that the use of all known effective interventions in 99 percent of children would only decrease stunting by about one-third," UVA's David Auble and his colleagues wrote in their paper. "For this reason, there is a pressing need to better understand the events that unfold on a molecular level in infants and give rise to the stunted phenotype, and to identify new targets and strategies for intervention."

The researchers analyzed blood samples collected as part of the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, a longitudinal study that has so far enrolled about 700 children during their first week of life and their mothers. Using chromatin immunoprecipitation combined with DNA sequencing (ChIP-seq), they examined the distribution and abundance of histone H3 lysine 4 trimethylation (H3K4me3) throughout the children's genomes.

As expected, the researchers noted H3K4me3 signals were enriched near transcription start sites, but as the children got older, this pattern changed in the children experiencing stunting, which is typically noticeable by two years of age. Rather than a global decrease in methylation, the researchers reported that a shift occurred: methylation moved from near the TSSs to other regions. This alteration, they noted, correlated with the children's HAZ score, a height and age-based measure of stunting.

By contrast, the researchers noted that histone H3 K27 acetylation showed no such stunting-related change.

They identified more than 5,500 differential H3K4me3 peaks associated with HAZ scores in the children. Peaks linked to poorer health included more than 900 that overlapped with promoters or enhancers active in blood or immune/cell types. These were particularly enriched for motifs recognized by members of the ETS1 and FOXO1 transcription factor families, which have roles in immune cell development and function and metabolism.

They also found that genes associated with peaks linked to better health were involved in protein, lipid, and carbohydrate metabolism as well as immune cell and immune system function. Similarly, they noted that peaks linked to better health included parts of the general transcription machinery like RNA polymerases I, II, and III, which suggested to the researchers that the overall transcription capacity of cells from stunted children was limited in comparison to unaffected children.

Based on RNA-seq data, the researchers found that one of the top genes affected by H3K4me3 changes in stunted children was LRP1. They suspected that LRP1 expression changes could contribute to stunting because of the gene's involvement in endocytic trafficking as well as in lipid metabolism and immune response.

In order to confirm this hypothesis, they performed digital droplet PCR and found that LRP1 expression was indeed reduced in stunted children. Additionally, the researchers found that mice lacking LRP1 had arrested growth as well as reduced fat and increased intestinal inflammatory macrophages. In all, they noted that the phenotypes exhibited by mice lacking LRP1 resembled those of stunted children, suggesting that reduced LRP1 expression could be behind the phenotype in people.

This gene, then, could represent a target for treatment, the authors noted.