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Immune and Metabolic Pathogenesis of Environmental Enteric Dysfunction in Childhood Undernutrition: A Birth Inception Cohort

ABSTRACT: Background: Environmental enteric dysfunction (EED) is a major impediment to the Sustainable Development Goals of improved childhood survival and healthy growth worldwide. Few studies have longitudinally and endoscopically examined EED in children, limiting the development of effective interventions. Methods: The Study of Environmental Enteropathy and Malnutrition (SEEM, Pakistan) followed 416 at-risk children prospectively from birth to 24 months of age in a rural district of Pakistan with a high prevalence of undernutrition. The duodenal genome-wide methylome and transcriptome was determined in 52 undernourished SEEM participants refractory to nutritional interventions and 42 North American pediatric controls and coeliac disease patients. Biomarkers were measured at 9 months and tested for association with growth at 24 months. Findings: The EED core transcriptome exhibited suppression of genes regulating antioxidant and detoxification functions and lipid metabolism, and induction of genes encoding anti-microbial responses, interferon signaling, and lymphocyte activation. Relative to coeliac disease, suppression of genes encoding antioxidant and detoxification functions and induction of anti-microbial responses were EED-specific. At the epigenetic level, EED was notable for hyper-methylation of genes involved in epithelial metabolism and barrier function, and hypo-methylation of genes involved in immune responses and cell proliferation. Duodenal co-expression modules revealed associations between genes regulating lymphocyte proliferation and epithelial metabolism with histologic severity, faecal energy loss, and wasting (weight-for-height Z<-2.0), with data supporting epigenetic regulation. Immune response genes were attenuated by Giardia colonization. After accounting for growth at study entry, IGF-1 and ferritin predicted linear growth, whereas leptin correlated with expression of epithelial carbohydrate metabolism and stem cell renewal genes, and weight gain. Interpretation: Data suggest immune and metabolic pathways which may inform more effective interventions to improve outcomes in EED. A validated model may be used to identify infants at greatest risk for future poor growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159495 | GEO | 2020/10/15

REPOSITORIES: GEO

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Project description:JARID2 ChIP-seq profile mediated by Xist was investigated using two separate approaches: In the first approach, we use the TX1072 female embryonic stem cell (ESC) line; this is a genetically polymorphic ESC line derived from a mouse with one X-chromosome (X-chr) from the Mus musculus castaneus (Cast) origin and the other of Mus musculus domesticus, C57BL/6 (BL6) strain origin, containing an inducible promoter on the BL6 Xist allele; differentiation and simultaneous induction of Xist for 4 days results in the inactivation of ONLY the BL6-derived X-chr and coating by JARID2 protein. We analysed this ESC line in the undifferentiated state, in which both X-chrs are active (and not coated by JARID2), and also after 4 days of differentiation under Xist inducible conditions, in which cells display one inactive X-chr from BL6 origin and one Xa of the Cast origin; the presence of SNPs allows for the comparison of the degree and localisation of JARID2 enrichment on the inactive X-chr versus the active X-chr; our results suggests that JARID2 is enriched on the inactive X-chr chromosome-wide and not in confined peaks as elsewhere in the genome; This pattern resembles patterns of Xist enrichment published before (Engreitz et al., 2013). In the second approach, we use a male ESC line that carries an inducible Xist transgene (TG) on chromosome 11 (chr11) (Wutz et al., 2000) in the presence (36:11 WT) or the absence of Eed (36:11 Eed-/-) Induction of Xist TG results in Xist coating and enrichment of JARID2 across the chr11, regardless of the presence of Eed when assess by IF/Xist RNA FISH experiments. We compare inducible and uninducible condition in both the 36:11 WT and Eed-/- ESCs; this way, we could assess the Xist-mediated JARID2 recruitment and the effect of the absence of Eed-/-; Our results shows that Xist induction result in a chromosome-wide enrichment of JARID2 on chr11, in a manner that resembles enrichment on the inactive X-chr; this pattern seem to be independent of EED, showing that in contrast to other regions in the genome where JARID2 occupancy is abrogated in the absence of EED, Xist-mediated JARID2 recruitment is not affected. JARID2 ChIP-seq analysis in differentiating female ESCs (TX1072) and in a male ESC harbouring a Xist transgene on chromosome 11 in WT and Eed-/- genetics settings

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Immune and Metabolic Pathogenesis of Environmental Enteric Dysfunction in Childhood Undernutrition: A Birth Inception Cohort

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