Sox9 transcriptionally regulates Wnt signaling in intestinal epithelial stem cells in hypomethylated crypts in the diabetic state

Abstract

BackgroundDistinctive structures called crypts harbor intestinal epithelial stem cells (IESCs) which generate progenitor and terminally differentiated cells in the intestinal epithelium. Mammalian IESCs and their daughter cells require the participation of DNA methylation and the transcription factor Sox9 for proliferation and differentiation. However, the association between Sox9 and DNA methylation in this process remains elusive.MethodsThe DNA methylation of small intestinal epithelial crypts in db/db mice was detected via combining methylated DNA immunoprecipitation with microarray hybridization. DNA methylation of Sox9 promoter in crypts and IESCs was validated using bisulfite sequence analysis. The target sequence of the transcription factor Sox9 in IESCs was investigated via chromatin immunoprecipitation (ChIP) combined with deep sequencing (ChIP-seq).ResultsIncreased Sox9 expression is accompanied by the loss of methylation in its promoter in IESCs. Sox9 targets the enhancers of the Wnt signaling pathway-related genes. Sox9 predominantly acts as a transcriptional activator at proximal enhancers of Wnt4, Tab2, Sox4, and Fzd8, but also functions as a potential transcriptional inhibitor at a distant enhancer of Cdk1. Lack of Sox9 transcriptional activation in specific repressors of the Wnt signaling pathway leads to the loss of intrinsic inhibitory action and ultimately produces overactivation of this pathway in db/db mice.ConclusionsOur study sheds light on the connections among DNA methylation, transcription factor modulation, and Wnt signaling in IESCs in the diabetic state. Hypomethylation in the Sox9 promoter is correlated to increased Sox9 expression in db/db IESCs. Although there is increased expression of Sox9 in db/db IESCs, the loss of Sox9 transcriptional activation in specific repressors of the Wnt signaling pathway might result in abnormalities in this pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0507-4) contains supplementary material, which is available to authorized users.

Decreased expression of microRNA‑145 promotes the biological functions of fibroblasts in hypertrophic scar tissues by upregulating the expression of transcription factor SOX‑9

“…SOX-9 is a member of the SOX gene family, which is closely associated with the proliferation, apoptosis and differentiation of cells (30). For example, SOX-9 gene transcription regulates the activity of the wnt signaling pathway in intestinal epithelial stem cells (31). In addition, SOX-9 promotes the proliferation, migration and differentiation of multiple tumor cells, including lung cancer, thyroid carcinoma and gastric cancer (32).…”

Transcription factor profiling identifies Sox9 as regulator of proliferation and differentiation in corneal epithelial stem/progenitor cells

“…Importantly, it has been suggested that Sox9 may regulate stem cell function through transcriptional modulation of genes involved in Wnt signaling 52 , 53 . While Sox genes clearly have Wnt independent roles, there are numerous reports in the literature, where Sox and Wnt are implicated in the same biological processes.…”

Rspo3 regulates the abnormal differentiation of small intestinal epithelial cells in diabetic state

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