Systemic interindividual DNA methylation variants in cattle share major hallmarks with those in humans

Authors: CHANG, WEN-JOU - Children'S Nutrition Research Center (CNRC); BAKER, MARIA - Children'S Nutrition Research Center (CNRC); LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); GUNASEKARA, CHATHURA - Children'S Nutrition Research Center (CNRC); MADURANGA, UDITHA - Children'S Nutrition Research Center (CNRC); GALLIOU, JUSTINE - Cornell University; MCFADDEN, JOSEPH - Cornell University; WALTEMYER, JESSICA - Cornell University; BERGGREN-THOMAS, BRUCE - Cornell University; TATE, BRIANNA - Cornell University; ZHANG, HANXUE - Cornell University; ROSEN, BENJAMIN - US Department Of Agriculture (USDA); VAN-TASSELL, CURTIS - US Department Of Agriculture (USDA); LIU, GEORGE - US Department Of Agriculture (USDA); COARFA, CRISTIAN - Baylor College Of Medicine; REN, YI ATHENA - Cornell University; WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: Genome Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/13/2024
Publication Date: 7/15/2024
Citation: Chang, W., Baker, M.S., Laritsky, E., Gunasekara, C.J., Maduranga, U., Galliou, J.C., McFadden, J.W., Waltemyer, J.R., Berggren-Thomas, B., Tate, B.N., Zhang, H., Rosen, B.D., Van-Tassell, C.P., Liu, G.E., Coarfa, C., Ren, Y., Waterland, R.A. 2024. Systemic interindividual DNA methylation variants in cattle share major hallmarks with those in humans. Genome Biology. 25. Article 185. https://doi.org/10.1186/s13059-024-03307-6.
DOI: https://doi.org/10.1186/s13059-024-03307-6

Interpretive Summary: Epigenetics is a system for molecular marking of DNA – it tells the different cells in the body which genes to turn on or off in that cell type. There is great interest in understanding epigenetic causes of disease and other individual characteristics. But the cell-specific nature of epigenetics makes it challenging to study. Whereas a blood sample can be used to ‘genotype’ an individual, most epigenetic marks in blood DNA provide no clues about epigenetic dysregulation in other parts of the body, such as the brain or heart. To overcome this obstacle, in 2019 we discovered special regions in the human genome where a blood sample can be used to infer epigenetic regulation throughout the body, allowing scientists to test for epigenetic causes of disease. Our analyses focused on the most stable form of epigenetic regulation – DNA methylation. The nearly 10,000 regions we mapped out in humans, called correlated regions of systemic interindividual variation (CoRSIVs), comprise a previously unrecognized level of molecular individuality in humans. Now, we have shown that CoRSIVs also exist in the cattle genome. Using publicly available data on genome-wide DNA methylation profiling in multiple tissues of each of two Holstein cattle, we identified over 200 cattle CoRSIVs. Then, using tissues from a separate set of Holstein cattle, we independently validated a subset of the CoRSIVs we identified. We showed that, just like at human CoRSIVs, establishment of DNA methylation at these regions is influenced by genetic variation, and by the environment of the early embryo. This discovery establishes a new level of molecular individuality that may be linked to agriculturally important traits such as milk production or disease resistance. Moreover, the similarities of cattle and human CoRSIVs suggest that CoRSIVs are likely a general feature of the mammalian genome, meaning that such opportunities for agricultural improvement may extend beyond cattle.

Technical Abstract: We recently identified'~'10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle. Focusing on genomic blocks with'='5 CpGs and a systemic interindividual variation index of at least 20, our approach identifies 217 cattle CoRSIVs, a subset of which we independently validate by bisulfite pyrosequencing. Similar to human CoRSIVs, those in cattle are strongly associated with genetic variation. Also as in humans, we show that establishment of DNA methylation at cattle CoRSIVs is particularly sensitive to early embryonic environment, in the context of embryo culture during assisted reproduction. Our data indicate that CoRSIVs exist in cattle, as in humans, suggesting these systemic epigenetic variants may be common to mammals in general. To the extent that individual epigenetic variation at cattle CoRSIVs affects phenotypic outcomes, assessment of CoRSIV methylation at birth may become an important tool for optimizing agriculturally important traits. Moreover, adjusting embryo culture conditions during assisted reproduction may provide opportunities to tailor agricultural outcomes by engineering CoRSIV methylation profiles.