TY - JOUR
T1 - Epigenetic maturation in colonic mucosa continues beyond infancy in mice
AU - Kellermayer, Richard
AU - Balasa, Alfred
AU - Zhang, Wenjuan
AU - Lee, Stefi
AU - Mirza, Sherin
AU - Chakravarty, Abrita
AU - Szigeti, Reka
AU - Laritsky, Eleonora
AU - Tatevian, Nina
AU - Smith, C. Wayne
AU - Shen, Lanlan
AU - Waterland, Robert A.
N1 - Funding Information:
R.K. was supported by funding from the Broad Medical Research Program, the Broad Foundation (IBD-0252) and a young investigator joint award from the Crohn’s and Colitis Foundation of America-Children’s Digestive Health and Nutrition Foundation/North American Society of Pediatric Gastroenterology Hepatology and Nutrition (CCFA Ref #2426). This work was also supported by NIH grant R01-DK081557, research grant #1-FY08-392 from the March of Dimes Foundation, and USDA CRIS #6250-51000-055 to R.A.W. DNaseI mapping data were funded through NHGRI ENCODE grant U54HG004592 to John Stamatoyannopoulos, University of Washington.
PY - 2010/3/2
Y1 - 2010/3/2
N2 - 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 (R2 = 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. Transcript Profiling: Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), accession numbers: GSE18031 (DNA methylation arrays), GSE19506 (gene expression arrays).
AB - 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 (R2 = 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. Transcript Profiling: Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), accession numbers: GSE18031 (DNA methylation arrays), GSE19506 (gene expression arrays).
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U2 - 10.1093/hmg/ddq095
DO - 10.1093/hmg/ddq095
M3 - Article
C2 - 20197410
AN - SCOPUS:77953597976
SN - 0964-6906
VL - 19
SP - 2168
EP - 2176
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 11
M1 - ddq095
ER -