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The Role of DNA Methylation in Gastrointestinal Smooth Muscle Cell Development & Plasticity
AuthorJorgensen, Brian G.
Biochemistry and Molecular Biology
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Methylation of genomic DNA at cytosines is a reversible and dynamic epigenetic mark that can modulate gene expression and cellular identity. Various gastrointestinal (GI) diseases have been associated with genomic hypomethylation but a detailed understanding of this correlation as it pertains to individual GI cell types has been lacking. Using transcriptome level data from isolated GI cells, it was found that the most highly expressed genes in GI smooth muscle cells (GI-SMC) that catalytically involved with DNA methylation were Dnmt3a, Dnmt1, & Tet2. Through the use of murine models, the DNA methyltransferases Dnmt1 & Dnmt3a, as well as the methylcytosine deoxygenase, Tet2, were selectively removed from the genome of GI-SMC with knockout of Dnmt1 showing the most promise. Congenital knockout of Dnmt1 (cDnmt1-KO) in GI-SMC produces smaller pups with a shorter GI tract, reductions in necessary smooth muscle transcripts (Myh11, Srf, Acta2, mir-143-145), global genomic hypomethylation, and apoptosis of GI-SMC resulting in severe intestinal dilation, lack of peristaltic movement, and death around P21. Upon introduction of a diet that is rich in specific methyl donating nutrients (MDN), cDnmt1¬-KO pups live one week longer than average, suggesting the possibility of enzymatic compensation through other DNMT isoforms (Dnmt3a, Dnmt3b), as has been previously reported in other intestinal cell types. Inducible Dnmt1-KO (iDnmt1-KO) mice do not produce the detrimental phenotype found in cDnmt1-KO mice as they only show a slight reduction in necessary smooth muscle markers (Myh11, Srf) which return to normal levels ~2 weeks after KO. However, when a partial intestinal obstruction is surgically introduced to iDnmt1-KO mice, massive intestinal dilation and lack of GI functioning occurs similar to that found in cDnmt1-KO. Taken together, these data show that aberrant changes to DNA methylation patterns in GI-SMC leads to various levels of phenotypic severity that are dependent upon several components including diet, genetics, epigenetics, and presence of obstruction.