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DNA Methyltransferase 1 Is Essential For Differentiation Of Gastrointestinal Smooth Muscle, But Not Required For Maintaining The Differentiated State In Mus Musculus.
AuthorBerent, Robyn Marie
Biochemistry and Molecular Biology
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In gastrointestinal (GI) motility disorders, there is abnormal functioning and gene expression in smooth muscle cells (SMCs). The phenotype of SMCs is regulated by SMC-specific genes, transcription factors (i.e.-serum response factor, SRF), and SRF-linked microRNAs (miRNAs). The promoters of tissue-specific genes and miRNAs contain large numbers of C-G dinucleotides compared to the rest of the genome (called CpG islands), which can accept methyl groups that will turn off downstream gene expression (called methylation). DNA methylation is essential for gastrulation of GI immature SMCs to differentiate into mature SMCs. The role of methylation in the development of GI motility disorders has yet to be elucidated. We hypothesize that a loss of methylation from CpG islands results in hypertrophied SM layers in the GI tract, with alterations in miRNA expression and gene expression compared to differentiated SMCs. In order to test our hypothesis, we generated a congenital and an inducible knock-out (KO) murine model of in vivo DNMT1 loss under the smooth muscle myosin heavy chain (smMyh11) promoter. Progressive phenotypic changes in the smooth muscle (SM) layer of the small intestine (SI) of congenital KO mice showed dilation of the SI, and degenerated SMCs with a progressive thinning of the SM layer. Deep sequencing of the mouse genome found an upregulation in anti-proliferative and pro-apoptotic miRNA and mRNA transcripts. However, the inducible KO mice did not develop a phenotype up to 6 months following tamoxifen injections. Additionally, we received human rectal prolapse samples and found decreased DNMT1 expression compared to control tissue samples, suggesting that DNMT1 plays an important role in the development of proliferative GI motility disorders. We conclude that DNMT1 is critical for proper development in immature SMCs, but is not required to maintain differentiation in mature SMCs.