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. 2010 Jun 1;19(11):2168-76.
doi: 10.1093/hmg/ddq095. Epub 2010 Mar 2.

Epigenetic maturation in colonic mucosa continues beyond infancy in mice

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Epigenetic maturation in colonic mucosa continues beyond infancy in mice

Richard Kellermayer et al. Hum Mol Genet. .

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. 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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Figures

Figure 1.
Figure 1.
Correlation between MSAM and pyrosequencing measurements of DNA methylation. An excellent correlation (R2 = 0.89) was detected between MSAM and pyrosequencing. The results are from 11 different SmaI/XmaI intervals in two independent P90 versus P30 comparisons.
Figure 2.
Figure 2.
Site specific CpG methylation in gene associated SmaI/XmaI intervals. Each gene diagram depicts the CpG density within the vicinity of the associated SmaI/XmaI interval. The shaded genomic regions are exons; horizontal arrows indicate TSSs, and vertical arrows point to the informative SmaI/XmaI sites. The graphs below the gene diagrams show individual CpG site (distance from TSS on x-axis) methylation levels (y-axis) for both the P90 (closed triangles), and P30 mice (open circles). Error bars were omitted if those were within or equal to the symbols. Vertical arrows point to the CpG of the informative SmaI/XmaI sites. The interruptions in the x-axis indicate multiple pyrosequencing assays used. N = 9–15 mice per age group in each assay.
Figure 3.
Figure 3.
Relative expression of galectin-1 (Lgals1). (A) Relative to P30, expression of Lgals1 decreased by half at P90 (P = 0.02, n = 13 per age). (B) Lgals1 expression is inversely correlated with Lgals1 DNA methylation (r = −0.50, n = 24, P = 0.013).
Figure 4.
Figure 4.
Expression of Stat1 decreases from P30 to P90. Relative to P30, the expression of Stat1 decreased by about half at P90 (n = 15 per age, P = 0.04).

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