Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging.

Area of Science:

• Genetics
• Epigenetics
• Mammalian Physiology

Background:

• Lactose digestion relies on the lactase gene, which is typically downregulated in adult mammals.
• Lactase persistence, the ability to digest lactose into adulthood, is a notable exception in some human populations.
• The mechanisms driving age-related lactase gene downregulation and its persistence in certain groups remain unclear.

Purpose of the Study:

• To investigate the epigenetic mechanisms underlying age-related changes in lactase gene expression.
• To identify regulatory elements controlling lactase mRNA levels across individuals, cell types, and species.
• To elucidate the interplay between genetic factors and epigenetic modifications in lactase persistence.

Main Methods:

• Comprehensive epigenetic study using chromosome-wide DNA-modification profiling.
• Targeted bisulfite sequencing of regulatory elements in human and mouse small intestines.
• CRISPR-Cas9-induced deletions to assess the functional role of regulatory elements.

Main Results:

• Epigenetically controlled regulatory elements were identified as key determinants of lactase mRNA levels.
• These regulatory elements showed differential epigenetic aging between lactase-persistent and non-persistent DNA haplotypes.
• CRISPR-Cas9 deletions confirmed the role of these elements in modulating lactase mRNA.

Conclusions:

• Epigenetic modifications at regulatory elements significantly influence lactase gene expression.
• Genetic factors play a crucial role in the age-dependent accumulation of epigenetic changes.
• This interplay between genetics and epigenetics explains variations in lactase persistence and phenotypic outcomes.