Edematous severe acute malnutrition is characterized by hypomethylation of DNA

Authors: SCHULZE, KATHARINA - Children'S Nutrition Research Center (CNRC); SWAMINATHAN, SHANKER - Children'S Nutrition Research Center (CNRC); HOWELL, SHARON - University Of The West Indies; JAJOO, AARTI - Children'S Nutrition Research Center (CNRC); LIE, NATASHA - Children'S Nutrition Research Center (CNRC); BROWN, ORGEN - University Of The West Indies; SADAT, ROA - Children'S Nutrition Research Center (CNRC); HALL, NANCY - Children'S Nutrition Research Center (CNRC); MARSHALL, KWESI - University Of The West Indies; MAY, THADDAEUS - Children'S Nutrition Research Center (CNRC); REID, MARVIN - University Of The West Indies; TAYLOR-BRYAN, CAROLYN - University Of The West Indies; WANG, XUEQING - Children'S Nutrition Research Center (CNRC); BELMONT, JOHN - Children'S Nutrition Research Center (CNRC); GUAN, YONGTAO - Children'S Nutrition Research Center (CNRC); MANARY, MARK - Washington University; TREHAN, INDI - Washington University; MCKENZIE, COLIN - University Of The West Indies; HANCHARD, NEIL - Children'S Nutrition Research Center (CNRC)

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/6/2019
Publication Date: 12/19/2019
Citation: Schulze, K.V., Swaminathan, S., Howell, S., Jajoo, A., Lie, N.C., Brown, O., Sadat, R., Hall, N., Marshall, K., May, T., Reid, M.E., Taylor-Bryan, C., Wang, X., Belmont, J.W., Guan, Y., Manary, M.J., Trehan, I., McKenzie, C.A., Hanchard, N.A. 2019. Edematous severe acute malnutrition is characterized by hypomethylation of DNA. Nature Communications 10(1):5791 https://doi.org/10.1038/s41467-019-13433-6
DOI: https://doi.org/10.1038/s41467-019-13433-6

Interpretive Summary: We have identified significant differences at the epigenetic level,the chemical tags in DNA that help regulate gene expression, between the two different forms of acute childhood malnutrition, known as edematous severe acute malnutrition (ESAM) and non-edematous SAM (NESAM). ESAM is characterized by body swelling and extensive dysfunction of multiple organs, including liver, blood cells and the gut, as well as skin and hair abnormalities. NESAM, on the other hand, typically presents with weight loss and wasting. The differences between ESAM and NESAM are still not fully explained despite decades of studies addressing this question. We found that ESAM, but not NESAM, is characterized by a reduction in methyl chemical tags in DNA and complex changes in gene activity, including both enhanced and reduced gene expression. Some of the genes that lost their methyl tags have been linked to other disorders of nutrition and metabolism, such as abnormal blood sugar and fatty liver disease, conditions that also have been observed in ESAM. The findings support consideration of methyl-group supplementation in ESAM.

Technical Abstract: Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includeskwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM(NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolismhave been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypo-methylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.