A new study on the epigenetics of lactose intolerance may offer a useful framework for exploring schizophrenia and other complex, serious illnesses.
Both lactose intolerance and schizophrenia are inherited conditions that typically do not appear during early childhood but emerge years or even decades later. That parallel prompted researchers to investigate whether shared mechanisms — specifically the interplay between genetics and epigenetics — could explain the delayed onset of these disorders, says Dr. Arturas Petronis, senior author and head of the Krembil Family Epigenetics Laboratory at the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH).
Published in Nature Structural and Molecular Biology, the study shows that a combination of DNA sequence variation and age-dependent epigenetic changes can explain why most adults lose the ability to digest lactose while some retain it. Those same basic molecular principles — the gradual accumulation of epigenetic marks that change gene activity over time in a genotype-dependent way — may be relevant for more complex brain disorders such as schizophrenia, bipolar disorder and Alzheimer’s disease, all of which involve genetic risk factors yet often manifest clinically only after many years.
Globally, more than 65 percent of adults are lactose intolerant and cannot fully digest the milk sugar lactose. Lactose intolerance is governed largely by the lactase gene (LCT), which in many people becomes progressively downregulated with age. People carrying certain genetic variants produce progressively less lactase enzyme over time, and eventually experience symptoms when lactase expression falls below the level needed to digest dietary lactose.
“Why does this change occur over time?” asks Dr. Petronis. “All newborns are able to digest lactose regardless of their genetic variants. Our findings reveal that epigenetic factors accumulate at different rates depending on an individual’s lactase gene variants.”
Over the course of life, these epigenetic modifications can build up and effectively switch off the lactase gene in some individuals but not in others. When enough inactivating changes accumulate, lactase production drops and lactose intolerance symptoms begin to appear.
Mapping how epigenetic control operates at the lactase gene required a multi-institutional collaboration between CAMH, the University of Toronto, The Hospital for Sick Children, Vilnius University and the Lithuanian University of Health Sciences. The team combined chromosome-wide DNA modification profiling and targeted bisulfite sequencing in human and mouse intestinal tissue, and used CRISPR–Cas9 genome editing to test the functional importance of identified regulatory elements.
While mental illnesses involve many more genes and much more complex regulatory landscapes than the single-gene trait of lactase persistence, the underlying concept is similar: genetic variation can shape the rate and pattern of age-related epigenetic change at key regulatory sites, and those gradual changes can influence whether and when a disease phenotype emerges. In other words, genotype-dependent epigenetic aging offers a plausible mechanism to explain delayed disease onset.
“By studying how the lactase gene is regulated across the lifespan in intestines, we developed hypotheses and gained insights that may point to comparable risk mechanisms in brain disorders,” Dr. Petronis explains. This approach highlights how a clearly defined biological model — lactase nonpersistence — can serve as a tractable system for exploring broader questions about genetic risk, epigenetic aging and late-onset disease.
Funding: This research was supported by the Canadian Institutes of Health Research, the National Institutes of Health and Brain Canada.
Source: Kate Richards – CAMH
Image Source: The image is in the public domain.
Original Research: Abstract for “Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging” by Viviane Labrie, Orion J Buske, Edward Oh, Richie Jeremian, Carolyn Ptak, Giedrius Gasiūnas, Almantas Maleckas, Rūta Petereit, Aida Žvirbliene, Kęstutis Adamonis, Edita Kriukienė, Karolis Koncevičius, Juozas Gordevičius, Akhil Nair, Aiping Zhang, Sasha Ebrahimi, Gabriel Oh, Virginijus Šikšnys, Limas Kupčinskas, Michael Brudno and Arturas Petronis in Nature Structural & Molecular Biology. Published online May 9, 2016. DOI: 10.1038/nsmb.3227
Abstract
Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging
The inability to digest lactose arises from lactase nonpersistence and is common among adult mammals, with certain human populations displaying lactase persistence. The mechanism by which the lactase gene is strongly downregulated with age in most individuals but remains active in others has been unclear. This study performed a comprehensive epigenetic analysis of human and mouse small intestine using chromosome-wide DNA-modification profiling and targeted bisulfite sequencing. The investigators found that epigenetically controlled regulatory elements explain differences in lactase mRNA levels between individuals, among intestinal cell types and across species. CRISPR–Cas9-induced deletions confirmed the functional relevance of these regulatory elements in modulating lactase expression. Genetic variation influences the pattern of age-associated epigenetic change at these regulatory elements: lactase-persistence and lactase-nonpersistence DNA haplotypes displayed markedly different trajectories of epigenetic aging. These results indicate that DNA variation can enable a gradual accumulation of epigenetic changes over time, thereby affecting phenotypic outcomes such as lactase persistence or nonpersistence.
“Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging” by Viviane Labrie et al., Nature Structural & Molecular Biology. Published online May 9, 2016. DOI: 10.1038/nsmb.3227