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

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.

Dynamic Signatures of the Epigenome: Friend or Foe?

“…promoter and enhancer, whose hypermethylation correlated with reduced lactase expression and activity, and consequently, with lactase non-persistence [36,63]. Of note, DMRs were also highly associated with known LCT polymorphism, suggesting the genetic influence on the epigenetic trait.…”

“…Of note, DMRs were also highly associated with known LCT polymorphism, suggesting the genetic influence on the epigenetic trait. However, the methylation level within the promoter and enhancer outperformed the genotype in the phenotype prediction test, which was particularly evident for SNP heterozygotes [36]. Another epigenetic trait associated with human adaptation is the evolution of molecular defense mechanisms.…”

“…Nevertheless, the influence of germline epimutation on evolution remains debatable. Epigenetic changes are frequently coupled with genetic variability [34][35][36][37], which poses questions about the driver function of epimutation. It is challenging to develop an appropriate research model for studying epimutation-driven transgenerational evolution.…”

“…The majority of mammals lose the ability to digest lactose after weaning, which suggests that epigenetic changes contribute to the shift in phenotype. In some human populations, lactase-the enzyme responsible for cleaving lactose into monosaccharides-is highly active throughout the whole life due to the polymorphisms within the lactase gene (LCT) enhancer [36]. High-throughput methylome profiling identified DMRs in the LCT promoter and enhancer, whose hypermethylation correlated with reduced lactase expression and activity, and consequently, with lactase non-persistence [36,63].…”

New insights into the molecular basis of lactase non-persistence/persistence: a brief review

“…-13910*T allele in genetically homogenous populations appears to be dominant, leading complete correlation of LP with the presence of the variant allele and tri-modal distribution in lactase enzymatic activities. However, methylation at the LCT enhancer and the LCT promoter are both affected by the genotype at rs4988235, and appear to be continuously associated with lactase phenotypes in heterogeneous populations (73). DNA methylation, rather than differential regulation of intestinal transcription factors like CDX2, POU2F1, GATA4/6 or HNF1α, in the enhancer and promoter site of the LCT gene was predictive of LNP/LP as indicated by regression (73).…”