Reprogramming of the intestinal epigenome by surgical tissue transposition
- Fides D Lay1,
- Timothy J Triche1,
- Yvonne C Tsai1,
- Sheng-Fang Su1,
- Sue Ellen Martin1,
- Siamak Daneshmand1,
- Eila C Skinner2,
- Gangning Liang1,
- Yoshitomo Chihara3 and
- Peter A Jones1,4
- ↵* Corresponding author; email: pjones{at}med.usc.edu
Abstract
Extracellular cues play critical roles in the establishment of the epigenome during development and may also contribute to epigenetic perturbations found in disease states. The direct role of local tissue environment on the post-development human epigenome, however, remains unclear due to limitations of studies in human subjects. Here, we use an isogenic human ileal neobladder surgical model where we compare global DNA methylation levels of intestinal epithelial cells pre- and post-neobladder construction using the Infinium HumanMethylation450 BeadChip. Our study is the first to quantify the effect of environmental cues on the human epigenome and show that the local tissue environment directly modulates DNA methylation patterns in normal differentiated cells in vivo. In the neobladder, the intestinal epithelial cells lose their tissue-specific epigenetic landscape in a time-dependent manner following the tissue's exposure to a bladder environment. We find that de novo methylation of many intestine-specific enhancers occurs at the rate of 0.41% per month (p <0.01, Pearson=0.71), while demethylation of primarily non-intestine specific transcribed regions occurs at the rate of-0.37% per month (p<0.01, Pearson=-0.57). The dynamic resetting of DNA methylome in the neobladder not only implicates local environmental cues in the shaping and maintenance of the epigenome, but also illustrates an unexpected cross-talk between the epigenome and cellular environment.
- Received September 9, 2013.
- Accepted February 6, 2014.
- Published by Cold Spring Harbor Laboratory Press
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