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Nat Struct Mol Biol. 2016 Jun;23(6):566-73. doi: 10.1038/nsmb.3227. Epub 2016 May 9.

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

Author information

1
Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
2
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
3
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
4
Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
5
Centre for Computational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
6
Department of Protein-DNA Interactions, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
7
Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania.
8
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
9
Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
10
Department of Biological DNA Modification, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
11
Institute of Mathematics and Informatics, Vilnius University, Vilnius, Lithuania.

Abstract

The inability to digest lactose, due to lactase nonpersistence, is a common trait in adult mammals, except in certain human populations that exhibit lactase persistence. It is not known how the lactase gene is dramatically downregulated with age in most individuals but remains active in some individuals. We performed a comprehensive epigenetic study of human and mouse small intestines, by using chromosome-wide DNA-modification profiling and targeted bisulfite sequencing. Epigenetically controlled regulatory elements accounted for the differences in lactase mRNA levels among individuals, intestinal cell types and species. We confirmed the importance of these regulatory elements in modulating lactase mRNA levels by using CRISPR-Cas9-induced deletions. Genetic factors contribute to epigenetic changes occurring with age at the regulatory elements, because lactase-persistence and lactase-nonpersistence DNA haplotypes demonstrated markedly different epigenetic aging. Thus, genetic factors enable a gradual accumulation of epigenetic changes with age, thereby influencing phenotypic outcome.

PMID:
27159559
PMCID:
PMC4899171
DOI:
10.1038/nsmb.3227
[Indexed for MEDLINE]
Free PMC Article

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