Characterization of Expression in Mice of a Transgene Containing 3.3 kb of the Human Lactase-Phlorizin Hydrolase (LPH) 5′ Flanking Sequence

Baffour-Awuah, Nana Yaa; Delemarre, Eveline M.; Fujiwara, Yuko; Heijmans, Jarom; Boerwinkel, David F.; Algra, Selma O.; Fialkovich, John J.; Islam, Sehbanul; Bosse, Tjalling; Grand, Richard J.; Krasinski, Stephen D.; Montgomery, Robert K.

doi:10.1007/s10620-010-1480-2

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“…Using an unbiased epigenome-wide approach verified by targeted pyrosequencing, we have identified position cg20242066 (chr2: 136595261; hg19) as differentially methylated in the jejunum of lactase persistent and lactase non-persistent children and adolescents. This CpG is located in the region essential for spatio-temporal regulation of human LCT expression, which has been previously demonstrated by introducing a construct containing the sequence 3.3kbs upstream of the TSS in transgenic mice 39 . Linear regression analysis showed that DNA methylation at both the LCT promoter and enhancer is largely impacted by genotype at −13910C > T, with CC homozygotes having the highest, and TT homozygous individuals the lowest methylation levels.…”

Section: Discussionmentioning

confidence: 79%

Differences in DNA Methylation and Functional Expression in Lactase Persistent and Non-persistent Individuals

Leseva

Grand

Klett

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 79%