Abstract
In humans the expression of lactase changes during post-natal development, leading to phenotypes known as lactase persistence and non-persistence. Polymorphisms within the lactase gene (LCT) enhancer, in particular the −13910C > T, but also others, are linked to these phenotypes. We were interested in identifying dynamic mediators of LCT regulation, beyond the genotype at −13910C > T. To this end, we investigated two levels of lactase regulation in human intestinal samples obtained from New England children and adolescents of mixed European ancestry: differential expression of transcriptional regulators of LCT, and variations in DNA methylation, and their relation to phenotype. Variations in expression of CDX2, POU2F1, GATA4, GATA6, and HNF1α did not correlate with phenotype. However, an epigenome-wide approach using the Illumina Infinium HM450 bead chip identified a differentially methylated position in the LCT promoter where methylation levels are associated with the genotype at −13910C > T, the persistence/non-persistence phenotype and lactase enzymatic activity. DNA methylation levels at this promoter site and CpGs in the LCT enhancer are associated with genotype. Indeed, taken together they have a higher power to predict lactase phenotypes than the genotype alone.
Highlights
The small intestine absorbs molecules from the intestinal lumen through enterocytes, the predominant cell type of the intestinal columnar epithelium that possess microvilli to increase surface area for digestion
Through regression modeling we show that DNA methylation in the enhancer and promoter site of the lactase gene (LCT) gene, rather than differential regulation of intestinal transcription factors, e.g. CDX2, POU2F1, GATA4/6 or HNF1α, is predictive of lactase persistence/non-persistence
Based on their importance for LCT gene regulation, we investigated differential expression of the transcription factors (TFs) GATA4, GATA6, HNF1α and CDX2 between lactase persistent and non-persistent individuals
Summary
The small intestine absorbs molecules from the intestinal lumen through enterocytes, the predominant cell type of the intestinal columnar epithelium that possess microvilli to increase surface area for digestion. In the context of mouse intestinal development, Dnmt1-mediated maintenance of methylation has been shown to be essential for crypt ISC differentiation[11,12,13] Genes such as mouse lactase (Lct) are induced upon differentiation to enterocytes, with a corresponding decrease in DNA methylation at specific CpG sites[11]. Because of the high degree of conservation in expression patterns and regulatory mechanisms, it was feasible that DNA methylation plays an important role in regulation of human LCT This was confirmed by Labrie et al who identified epigenetically controlled regulatory elements where differential DNA methylation accounted for inter-individual differences of lactase mRNA level in a Lithuanian cohort of individuals[15]. Not the first investigation of DNA methylation as a molecular mechanism for the regulation of LCT expression[15], we have performed the first genome-wide DNA methylation profiling using intestinal tissues obtained from children and adolescents, with the youngest being 8 years old
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
