Location: Children's Nutrition Research CenterTitle: Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Author
Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2010
Publication Date: 3/2/2010
Citation: Kellermayer, R., Balasa, A., Zhang, W., Lee, S., Mirza, S., Chakravarty, A., Szigeti, R., Laritsky, E., Tatevian, N., Smith, W.C., Shen, L., Waterland, R.A. 2010. Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Human Molecular Genetics. 19(11):2168-2176. Interpretive Summary: Inflammatory bowel disease, specifically Crohn's disease and ulcerative colitis, impact more than 600,000 Americans every year. Susceptibility to inflammatory bowel disease was studied in mice at 30 and 90 days of age, to determine if susceptibility increases with age. The results revealed that 90 day old mice lost more weight and had more severe disease in their intestines than the younger mice. The lining of the intestine of the young and older mice was also evaluated for DNA methylation, a chemical change in DNA that is known to affect the ability of some genes to synthesize proteins. There was more DNA methylation in the older mice than in the young, suggesting that this chemical change in DNA may influence the susceptibility to inflammatory bowel disease. These research findings provide insight into the development of a disease that impacts many Americans.
Technical Abstract: Monozygotic twin and other epidemiologic studies indicate that epigenetic processes may play an important role in the pathogenesis of inflammatory bowel diseases that commonly affect the colonic mucosa. The peak onset of these disorders in young adulthood, suggests that epigenetic changes normally occurring in the colonic mucosa shortly before adulthood could be important etiologic factors. We assessed developmental changes in colitis susceptibility during the physiologically relevant period of childhood in mice [postnatal day 30 (P30) to P90], and concurrent changes in DNA methylation, and gene expression in murine colonic mucosa. Susceptibility to colitis was tested in C57BL/6J mice with the dextran sulfate sodium colitis model. Methylation specific amplification microarray (MSAM) was used to screen for changes in DNA methylation, with validation by bisulfite pyrosequencing. Gene expression changes were analyzed by microarray expression profiling and real time RT-PCR. Mice were more susceptible to chemically induced colitis at P90 than at P30. DNA methylation changes, however, were not extensive; of 23 743 genomic intervals interrogated, only 271 underwent significant methylation alteration during this developmental period. We found an excellent correlation between the MSAM and bisulfite pyrosequencing at 11 gene associated intervals validated (R (2) = 0.89). Importantly, at the genes encoding galectin-1 (Lgals1), and mothers against decapentaplegic homolog 3 or Smad3, both previously implicated in murine colitis, developmental changes in DNA methylation from P30 to P90 were inversely correlated with expression. Colonic mucosal epigenetic maturation continues through early adulthood in the mouse, and may contribute to the age-associated increase in colitis susceptibility.