title: Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging.
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.
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Viviane
authors.initials: V
authors.lastname: Labrie
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Centre for Computational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Orion J
authors.initials: OJ
authors.lastname: Buske
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Oh
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Richie
authors.initials: R
authors.lastname: Jeremian
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ptak
authors.affiliation: Department of Protein-DNA Interactions, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
authors.forename: Giedrius
authors.initials: G
authors.lastname: Gasiūnas
authors.affiliation: Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Almantas
authors.initials: A
authors.lastname: Maleckas
authors.affiliation: Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Rūta
authors.initials: R
authors.lastname: Petereit
authors.affiliation: Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.|Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Aida
authors.initials: A
authors.lastname: Žvirbliene
authors.affiliation: Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Kęstutis
authors.initials: K
authors.lastname: Adamonis
authors.affiliation: Department of Biological DNA Modification, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
authors.forename: Edita
authors.initials: E
authors.lastname: Kriukienė
authors.affiliation: Institute of Mathematics and Informatics, Vilnius University, Vilnius, Lithuania.
authors.forename: Karolis
authors.initials: K
authors.lastname: Koncevičius
authors.affiliation: Institute of Mathematics and Informatics, Vilnius University, Vilnius, Lithuania.
authors.forename: Juozas
authors.initials: J
authors.lastname: Gordevičius
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Akhil
authors.initials: A
authors.lastname: Nair
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Sasha
authors.initials: S
authors.lastname: Ebrahimi
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Oh
authors.affiliation: Department of Protein-DNA Interactions, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
authors.forename: Virginijus
authors.initials: V
authors.lastname: Šikšnys
authors.affiliation: Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.|Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Limas
authors.initials: L
authors.lastname: Kupčinskas
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Centre for Computational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Brudno
authors.affiliation: Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Arturas
authors.initials: A
authors.lastname: Petronis
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging; D000818:Animals; D064113:CRISPR-Cas Systems; D002875:Chromosomes / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007583:Jejunum / Q000201:enzymology / Q000378:metabolism; D043322:Lactase / Q000235:genetics*; D007787:Lactose Intolerance / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D043322:Lactase