While fine wine and aged cheese are culinary delights, some of us who dine on dairy often start to go a bit ‘sour’ with age and develop lactose intolerance. Thankfully, to aid our mental digestion of such a foul fate, a collaborative effort between Toronto and Lithuania has shown the molecular mechanism of why we can lose the ability to process lactose.
Lactase (LCT) is an enzyme that is involved in the digestion of lactose. Humans typically have high levels of lactase in their intestines in their younger years, which fades with age for 65% of people globally, although in the USA and a lot of Europe mutants who have persistent lactase expression during adulthood are the majority.
A C/T SNP in the MCM6 gene, which is next to LCT, has been homed in on by GWAS studies of lactase nonpersistence in Europeans. Interestingly, the T allele confers lactase persistence and is part of a haplotype that has been under evolutionary selection for the past few thousand years. However, as senior author Arturas Petronis puts it, “The question we asked is why does this change happen over time? All newborns are able to digest lactose, independently from their genetic variation.”
Here’s the digest:
- The team used mTAG-click with tiling arrays to identify unmodified DNA (as a proxy for DNA methylation) in human and mouse intestinal cells. They found that density of unmodified cytosines is correlated with expression of LCT, and that methylation accumulates with with age.
- The team then turned to higher-resolution bisulfite-padlock probe sequencing to zoom in on the region that gains methylation in humans as lactase expression decreases. Unlike intestinal cells, white blood cells showed no age-related methylation pattern.
- The team also examined the functionality of the locus by using RNAi to investigate an antisense lncRNA in a human cell line and CRISPR/Cas9 to induce some precision deletions to the identified regulatory elements in mice.
Overall, the study shows that lactose intolerance results from the age-related accumulation of DNA methylation by the wild type allele haplotype, while the mutant allele haplotype escapes the sands of the epigenetic clock.
While we can dream of a future utopia where somatic (epi)genome editing means we no longer have to tolerate lactose intolerance, the team has a bigger picture perspective. By understanding how sequence variation alters the deposition of epigenetic marks with age, we can begin to understand other diseases with a delayed age of onset, such as schizophrenia. Petronis concludes, “Now, we know that epigenetic factors accumulate at a very different pace in each person, depending on the genetic variants of the lactase gene. We came up with interesting hypotheses, and possibly insights, into risk factors for brain disease by studying aging intestines.”
Take a bite out of lactose intolerance over at Nature Structural & Molecular Biology, May 2016