Smad4 pathways modulate induction of the chemokine Ccl20 and repress inflammation-induced carcinogenesis in mouse colon
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100082 | GEO | 2018/06/01
REPOSITORIES: GEO
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Project description:Purpose: To understand how loss of epithelial Smad4 alters gene expression in mouse colon stroma Methods: To understand the extent of Smad-mediated gene regulation in the colon, we isolated colon epithelium from three Smad4ΔLrig1 and from three SMAD4+ control mice (either mice lacking a CreERT allele and treated with tamoxifen, or mice bearing a CreERT allele but treated with vehicle only) and analyzed the colonic stroma by RNAseq. Results: A comparison of gene expression within the sub-epithelial stroma of Smad4Lrig1 mice relative to SMAD4+ control mice demonstrated a marked increase in inflammatory gene signaling. Of the 95 genes that were upregulated by at least 2.5-fold (≥1.32 Log2 Fold Change) and a false discovery rate <0.05, 51 genes are known to be expressed on immune cells or have immune-related functions, including Ccr6. Conclusions: SMAD4 modulates inflammatory signaling in colonic stroma to repress colitis-associated tumor formation
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Project description:KSRP knock-down and BMP2 treatment produce a largely overlapping reshape of the transcriptome in C2C12 cells. microRNAs (miRNAs) are essential regulators of development, physiology, and evolution with miRNA biogenesis being strictly controlled at multiple levels. Regulatory proteins, such as KH-type splicing regulatory protein (KSRP), modulate rates and timing of the enzymatic reactions responsible for maturation of select miRNAs from their primary transcripts in response to specific stimuli. Induction of myogenic miRNAs (myomiRs) is essential for muscle differentiation with KSRP phosphorylation being required to convey myogenic signals to enhanced myomiR maturation. Here we show that either KSRP silencing or Bone Morphogenetic Protein (BMP)2-signaling activation in mesenchimal C2C12 cells prevented myogenic differentiation while induced osteoblastic differentiation as revealed by the reshaping of the whole transcriptome analyzed by RNA deep-sequencing. The most striking feature common to both BMP2 signaling activation and KSRP silencing was a blockade of myomiR maturation. Our results demonstrate that phosphorylated SMAD proteins, the transducers of BMP signaling, associate with KSRP and block its interaction with primary-myomiRs. This, in turn, abrogates KSRP-dependent myomiR maturation with the knock-down of SMAD4, 5, and 9 being able to rescue KSRP function. SMAD-induced blockade of KSRP-dependent myomiR maturation, in parallel to the well known SMAD function on gene transcription, inhibits C2C12 cell differentiation into myofibers and contributes to orient cells towards osteoblast lineage. We propose that remodeling of co-regulatory complexes affecting primary-miRNA processing is a mechanism well suited to guide cell fate determination in eukaryotes. Total RNA was prepared from 1. untreated mock-transfected C2C12 cells; 2. BMP2-treated mock-transfected C2C12 cells; 3. untreated shKSRP-transfected C2C12 cells and analyzed by RNA-seq
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2013-04-29 | GSE38103 | GEO