Required Enhancer: Matrin-3 Structure Interactions for Homeodomain Transcription Programs
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE58009 | GEO | 2014/08/03
SECONDARY ACCESSION(S): PRJNA248882
REPOSITORIES: GEO
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Project description:Study of the POU-homeodomain transcription factor, has revealed that, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer / coding gene transcriptional program. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of Matrin3 in the Homeodomain transcription study. Gro-seq Samples are used to detect gene expression between knockdown control and knockdown two key factors in our study.
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Project description:Matrin-3 is an RNA-binding protein involved in the pathogenesis of human diseases. Here we examined the hepatic transcriptome of chow-diet fed mice. Bulk RNA-seq and bioinformatics analysis identified 646 and 145 differentially expressed genes (Padj < 0.05), respectively in the livers of female and male matrin-3 LKO mice. Enrichr analysis of these DEGs revealed several common Hallmark terms including cholesterol homeostasis, fatty acid metabolism, xenobiotic metabolism, and epithelial mesenchymal transition between female and male mice. Our data demonstrated that liver-specific matrin-3 deficiency re-programs the hepatic transcriptome in the liver of chow diet-fed mice.
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Project description:Mutations in Matrin 3 have recently been linked to ALS, though the mechanism of disease in these patients is still unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry experiments in NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin in mRNA transport centered around proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and the mRNA of ALS linked proteins TDP-43 and FUS. Our findings demonstrate the first pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.
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Project description:Homeodomain proteins, described 30 years ago, exert essential roles in development as regulators of target gene expression; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-homeodomain transcription factor, Pit1 (also known as Pou1f1), has revealed that, unexpectedly, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer/coding gene transcriptional program. Pit1 association with Satb1 (ref. 8) and ?-catenin is required for this tethering event. A naturally occurring, dominant negative, point mutation in human PIT1(R271W), causing combined pituitary hormone deficiency, results in loss of Pit1 association with ?-catenin and Satb1 and therefore the matrin-3-rich network, blocking Pit1-dependent enhancer/coding target gene activation. This defective activation can be rescued by artificial tethering of the mutant R271W Pit1 protein to the matrin-3 network, bypassing the pre-requisite association with ?-catenin and Satb1 otherwise required. The matrin-3 network-tethered R271W Pit1 mutant, but not the untethered protein, restores Pit1-dependent activation of the enhancers and recruitment of co-activators, exemplified by p300, causing both enhancer RNA transcription and target gene activation. These studies have thus revealed an unanticipated homeodomain factor/?-catenin/Satb1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.
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Project description:Matrin-3 is an RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor. Matrin-3 expression was induced in the steatotic livers of mice and humans. Liver-specific matrin-3 knockout (LKO) exacerbated high-fat diet (HFD)-induced steatosis, acute phase response, and inflammation in the liver of mice. Bulk RNA-seq and bioinformatics analysis identified 1,333 and 239 differentially expressed genes (fold change > 1.5 & Padj < 0.05), respectively in the livers of female and male matrin-3 LKO mice. Gene Set Enrichment Analysis revealed that the top most enriched Gene Ontology Biological Process was the “Xenobiotic metabolic process” in female matrin-3 floxed mice that is downregulated. The top two enriched biological processes are “Acute inflammatory response” and “Acute phase response” in the liver of female LKO mice that are upregulated. Several GO terms related to lipid metabolism and xenobiotic metabolism were enriched in the livers of male mice. Real-time qPCR revealed that the expression of many genes involved in xenobiotic metabolism was reduced in the liver of female LKO mice and to a lesser extent in the liver of male LKO mice, while the expression of acute-phase response genes was induced in the liver of female but not male LKO mice. Our data demonstrated that liver-specific matrin-3 deficiency re-programs the hepatic transcriptome enriched for xenobiotic metabolism pathway, acute-phase and inflammatory response signaling in the liver of HFD-fed mice.
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Project description:Required Enhancer: Matrin-3 Structure Interactions for Homeodomain Transcription Programs
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Project description:Matrin-3 is an RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in regulating chromatin accessibility in the liver of mice. Bulk ATAC-seq and bioinformatics analysis identified 523 and 829 differential peaks (FDR < 0.05), respectively, in the liver of female mice fed a chow diet or 60% HFD for 16 weeks. Peak annotation by HOMER and ChIPseeker identified 183 and 444 genes, respectively, that are associated with the differential peaks. Enrichr analysis of these genes revealed that Hallmark terms such as "Xenobiotic metabolism" was enriched in the liver of chow-fed and HFD-fed mice. TRRUST database analysis from Metascape uncovered that Hnf4α is the main transcription factor regulating these peak-associated genes in the liver of chow-fed mice, and Hnf4α and Nr1i3 are the main transcription factors regulating these peak-associated genes in the liver of HFD-fed mice. Our data demonstrated that liver-specific matrin-3 deficiency alters chromatin accessibility likely affecting the action of two transcription factors Hnf4α and Nr1i3 in the liver of mice.
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