A new study on the epigenetics of lactose intolerance may provide an approach to understanding schizophrenia and other complex, serious illnesses.
Both lactose intolerance and schizophrenia are inherited. In addition, neither condition emerges in the first years of life, but rather both appear years or even decades later, says senior author Dr. Arturas Petronis, head of the Krembil Family Epigenetics Laboratory in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH).
The study, published in Nature Structural and Molecular Biology, showed that a combination of genetics and epigenetics – factors that turn genes on or off – could explain how lactose intolerance develops over time. These basic principles can be applied to the study of more complex mental illnesses such as schizophrenia, bipolar disorder or Alzheimer’s disease. All these conditions also have DNA risk factors but take decades before clinical symptoms develop, says Dr. Petronis, who also is the Tapscott Chair in Schizophrenia Studies at the University of Toronto.
More than 65 per cent of adults worldwide are lactose intolerant and cannot process the milk sugar lactose. Lactose intolerance is influenced by one gene, which determines if a person will lose the ability to process lactose over time. More specifically, those with some variants of this gene will gradually produce less lactase, the enzyme that breaks down lactose, as they age.
“The question we asked is why does this change happen over time? All newborns are able to digest lactose, independently from their genetic variation,” says Dr. Petronis. “Now, we know that epigenetic factors accumulate at a very different pace in each person, depending on the genetic variants of the lactase gene.”
Over time, these epigenetic changes build up and inactivate the lactase gene in some – but not all – individuals. At this point, these individuals would start experiencing symptoms of lactose intolerance.
Unravelling the epigenetic control of the lactase gene involved a collaborative effort of CAMH, University of Toronto, the Hospital for Sick Children, Vilnius University and the Lithuanian University of Health Sciences.
Mental illnesses are much more complex, and many more genes with their epigenetic “surroundings” are implicated. But in essence, the same molecular mechanisms may account for the delayed age of onset of illnesses, such as schizophrenia, in early adulthood, says Dr. Petronis.
The combination of genes and epigenetic factors that build up over time with age, provide a plausible avenue to investigate in illnesses such as schizophrenia. “We came up with interesting hypotheses, and possibly insights, into risk factors for brain disease by studying aging intestines,” he says.
Funding: Canadian Institutes of Health Research, National Institutes of Health, Brain Canada provided funding for this research.
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
Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging
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.
“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