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Sox9 transcriptionally regulates Wnt signaling in intestinal epithelium stem cells under hypomethylated crypts in diabetic state

ABSTRACT: Mammalian intestinal epithelium stem cells (IESCs) and their daughter cells require the participation of DNA methylation and the transcription factor Sox9 for proliferation and differentiation. Combining methylated DNA immunoprecipitation with microarray hybridization, we demonstrate that hypomethylation in promoter participates in the aberrant formation of crypts in diabetic db/db mice through ectopic Wnt signaling. More importantly, increased expression of Sox9 is accompanied by the loss of methylation in its promoter in IESCs. Using ChIP-seq analysis for Sox9 in IESCs, we demonstrate that Sox9 primarily targets the enhancers of Wnt signaling pathway-related genes. Sox9 is not only predominately acting as a transcriptional activator at proximal enhancer but also as a potential transcriptional inhibitor at distant enhancer. Lack of Sox9 transcriptional activation in specific repressors of Wnt signaling pathway results in loss of intrinsic inhibitory action and ultimately produces over-activation of this pathway in diabetes mellitus.

ORGANISM(S): Mus musculus

PROVIDER: GSE87044 | GEO | 2017/01/30

SECONDARY ACCESSION(S): PRJNA343302

REPOSITORIES: GEO

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Project description:Sivakumar2011_WntSignalingPathway The secreted protein Wnt activates the heptahelical receptor Frizzled on nieghboring cells. Activation of Frizzled causes the recruitment of additional membrane proteins which in turn result in 1) the activation of the protein Dishevelled via phosphorylation and 2) the activation of a heterotrimeric G protein of unknown type. Activation of Dishevelled results in the down-regulation of the Beta-Catenin destruction complex which causes ubiquitination of Beta-Catenin and its ultimate degradation via the proteasome. Inhibition of the Beta-Catenin destruction complex yields a higher cytosolic concentration of Beta-Catenin, which enters the nucleus, binds various transcriptional regulatory molecules including the TCF/LEF class of proteins, and results in the transcription of TCF/LEF target genes. Activation of the heterotrimeric G-protein pathway in turn activates Phospholipase C which in turn catalyzes the catalysis of PI(4,5)P2 into DAG and IP3. Reference: The Wnt signalling pathway. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Wnt signaling pathway. This model is described in the article: A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways. Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S. OMICS 2011 Oct; 15(10): 729-737 Abstract: The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs. This model is hosted on BioModels Database and identified by: BIOMD0000000397. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Sox9 transcriptionally regulates Wnt signaling in intestinal epithelium stem cells under hypomethylated crypts in diabetic state

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