Epigenetic maturation in colonic mucosa continues beyond infancy in mice

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).

Expression of Lactoperoxidase in Differentiated Mouse Colon Epithelial Cells

“…Age-dependent changes in DNA methylation have been observed in both humans and mice, with more genes hypermethylated than hypomethylated [27][28][29]. Here, we have identified Lpo gene to be hypermethylated through aging, mostly from juvenile to adult phase.…”

Maternal micronutrients can modify colonic mucosal microbiota maturation in murine offspring

“…22 Importantly, the physiologic mucosal bacterial maturation determined herein parallel both DNA methylation and gene expression changes and associate with an increased susceptibility to colitis in the same mouse strain (C57BL/6J). 8 The decreased abundance of Lactobacillus johnsonii for instance may These findings highlight prenatal and suckling MD supplementation induces remarkably modified colonic mucosal microbiota maturation compared with controls in mice despite of the two offspring groups receiving the same diets after weaning.…”

“…32 Colonic mucosal DNA methylation modifications specifically have been shown to associate with microbiota alterations in murine models of human IBD. 8,33 However, one must first understand physiologic changes during maturation to reveal the impact and possible consequences of modifications in such developmental processes.…”

“…Therefore, understanding the details of mammalian maturation and its environmental vulnerability within the key biologic components of IBD can provide insights into its pathogenesis. 8 We have recently shown that maternal methyldonor (MD: betaine, choline, folate, vitamin B12) supplementation can induce persistent microbiota changes in murine offspring in association with mucosal DNA methylation and gene expression alteration, and a significant increase in colitis susceptibility. 9 In this study, we examined the effects of MD supplementation on the maternal microbiota and interrogated the previous offspring data set in examined the effects of MD supplementation on fecal microbiota composition in female mice.…”

Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice

“…This intricacy is probably most astounding in humans where the "superorganism" can be envisioned as the result of the multiorganic articLe addenduM articLe addenduM 1b). [30][31][32] Not surprisingly, plasma folate levels have been related to fecal bacterial composition changes in pregnant women recently. 33 These studies on one single vitamin/micronutrient model and illustrate the close to incomprehensible complexity of host-environment interactions in the human "superorganism".…”