Twin, family, and adoption studies have surmounted numerous direct and circumstantial evidence supporting the gene-environment paradigm in human disease studies. In the last several decades, however, there is increasing realization that epigenetics, with its malleability and somatic heritability, can serve as a functional extension of genetic predispositions and mediator of environmental risk factors. In our laboratory, we have focussed on the less discussed epigenetic roles, i.e. phenotypic changes in the same genetic background such as disease dynamics and trajectories through the individual’s lifespan. Within individuals born with genetic risk factors, how do diseases stay “silent” for a number of decades only to manifest at specific ages? Even more surprising is partial or complete recovery, which may occur spontaneously, without eliminating the causes or application of curable clinical intervention. Patients affected by major psychosis, asthma or attention deficit and hyperactivity syndrome can show significant improvement after years or even decades of suffering from delusions and hallucinations, periods of obstructed breathing, and inability to focus, respectively. The question of phenotypic transformations on the same genetic background - a blind spot of the traditional paradigm in disease studies - is of central importance in epigenetics of disease. In fact, it is simply a new formulation of the primary prerogative of epigenetics which, from the times of C. H. Waddington, has attempted to understand the basic mechanisms of development - changes of cellular phenotypes in genetically identical cells of the same organism.
In 2020, we finalized on building the key principles for chrono-epigenetic (Greek “chronos” – time) disease research program in human disease, which puts a strong emphasis on the temporal aspects of epigenetic studies. Chrono-epigenetics can change our perceptions of the key axes and dimensions of health and disease - stability vs dynamics, stochasticity vs determinism, and external vs internal risk factors. We also proposed that investigating temporality and individuality of the epigenome can advance our understanding of phenotypic transformations of health to disease and back to health. Based on this, we propose a new rationale, guidelines, and experimental approaches for chrono-epigenetic and -epigenomic studies of disease, marking the advent of the 3rd generation of epigenome-wide association studies.
We have established collaboration with clinical scientists and started collecting biological samples for chrono-epigenetic studies of colorectal cancer and psychiatric disease. We have performed a series of wet lab and computational experiments, which provide further support for the chrono-epigenetic theory and help to optimize large-scale chrono-epigenomic studies.
- Labrie, V., Buske, O. J., Oh, E., Jeremian, R., Ptak, C., Gasiūnas, G., Maleckas, A., Petereit, R., Žvirbliene, A., Adamonis, K., Kriukienė, E., Koncevičius, K., Gordevičius, J., Nair, A., Zhang, A., Ebrahimi, S., Oh, G., Šikšnys, V., Kupčinskas, L., Brudno, M., Petronis, A. Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging. Nat Struct Mol Biol. 2016, 23(6): 566–73.
- Gagliano, S. A., Ptak, C., Mak, D. Y., Shamsi, M., Oh, G., Knight, J., Boutros, P. C., Petronis, A. Allele-skewed DNA modification in the brain: relevance to a schizophrenia GWAS. Am J Hum Genet. 2016, 98(5): 956–62.
- Oh, G., Ebrahimi, S., Carlucci, M., Zhang, A., Nair, A., Groot, D. E., Labrie, V., Jia, P., Oh, E. S., Jeremian, R. H., Susic, M., Shrestha, T. C., Ralph, M. R., Gordevičius, J., Koncevičius, K., Petronis, A. Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging. Nature Communications. 2018 Feb 13, 9(1): 644.
- Oh, G., Koncevičius, K., Ebrahimi, S., Carlucci, M., Groot, D. E., Nair, A., Zhang, A., Kriščiūnas, A., Oh, S. E., Labrie, V., Wong, A. H. C.,, Gordevičius, J., Jia, P., Susic, M., Petronis, A. Circadian oscillations of cytosine modification in humans contribute to epigenetic variability, aging, and complex disease. Genome Biology. 2019, 20(2): 2457.
- Petronis, A., Labrie, V. The crossroads of psychiatric epigenomics. World Psychiatry. 2019, 18(3): 353–354.