The LIN28B-IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA475675 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7293730.fastq.gz | Fastqsanger.gz | |||
| SRR7293731.fastq.gz | Fastqsanger.gz | |||
| SRR7293732.fastq.gz | Fastqsanger.gz | |||
| SRR7293729.fastq.gz | Fastqsanger.gz |
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Project description:Aim: RNA binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Method: Here we describe a novel interplay between RBPsLIN28B and IMP1 in intestinal epithelial cells. Ribosome-profiling and RNA-sequencing identifies IMP1 as a principle nodefor gene expression regulation downstream of LIN28B. Results: In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild type or LIN28B-overexpressing mice enhancesthe regenerative response to irradiation. Conclusions: Together, our data provide new evidence for the opposing effects of the LIN28B-IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.
2018-12-27 | GSE115647 | GEO
Project description:RNA-binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Here we describe a novel interplay between RBPs LIN28B and IMP1 in intestinal epithelial cells. Ribosome profiling and RNA sequencing identified IMP1 as a principle node for gene expression regulation downstream from LIN28B In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild-type or LIN28B-overexpressing mice enhances the regenerative response to irradiation. Together, our data provide new evidence for the opposing effects of the LIN28B-IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.
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Project description:Isolation of IMP1 bound mRNAs. Flag-tagged IMP1 was expressed in HEK293 cells. Flag tagged IMP1 was immunoprecipitated and mRNAs isolated. As controls HEK293 cells that do not express Flag-tagged IMP1 was included.
2006-12-31 | E-MEXP-841 | biostudies-arrayexpress
Project description:ZBP1/IMP1 is a RNA binding protein that post-transcriptionally regulates the expression of a handful mRNAs, implicated in maintaining cell polarity and adhesion. We have previously shown that ZBP1 was able to inhibit proliferation and invasiveness of breast carcinoma cells in vitro. To determine important LncRNA for breast tumor growth and metastasis in response to IMP1 expression, LncRNA expression data were obtained from, and compared between the breast cancer cell line MDA231-IMP1 and MDA231/GFP.
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Project description:The onco-fetal RNA-binding protein IMP1 is expressed in fetal liver HSCs, but down-regulated in adult BM HSCs. We here show that when IMP1 is re-expressed in adult HSCs it induces a significant part of the fetal HSC gene expression signature. In addition, IMP1 re-expression leads to the expansion of phenotypic long term (LT-)HSCs, and increased generation of fetal peritoneal B1a B-cells and thymic γδ-T-cells. Finally, IMP1 expressing adult LT-HSCs show dramatically improved self-renewal in serial transplantations compared to their normal counterparts. To assess the effect of IMP1 re-expression on the molecular properties of adult HSCs we performed RNA sequencing of total RNA isolated from Control and IMP1 HSCs sorted from primary recipient mice, transplanted with control or IMP1+ total bone marrow cells.
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Project description:IMP1 is a RNA binding protein shown to regulate translation, localization, or stability of their target RNAs. However, whether IMP1 can widely bind to lncRNAs and regulate their expression in Breast cancer cells remains to be confirmed. In this study, we used RNA binding protein immunoprecipitation-high throughput sequencing (RIP-Seq) technique to identify LncRNAs which bind to IMP1 protein in breast cancer cell line T47D cells.
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Project description:The RNA binding protein Lin28b is highly expressed during embryogenesis but its expression declines in adult tissues, and aberrant expression of Lin28b is associated with tumour development and maintenance. Lin28b regulates the translation of several glycolytic and mitochondrial enzymes in order to enhance cellular metabolism and energy production. Lin28b is repressed by let-7 family microRNAs in a reciprocal negative regulatory circuitry where Lin28b supresses maturation of let-7. This circuitry obtains input from master regulators such as MYC that transcriptionally upregulates Lin28b, which is required for let-7 suppression and proliferation. Not much is known of how this circuitry is regulated through transcription of the let-7 microRNAs. Here we show that the transcription factor C/EBPβ-LIP induces aerobic glycolysis and mitochondrial respiration reminiscent to cancer cell metabolism. By integrating transcriptome, proteome and metabolic flux analysis we reveal that this LIP-induced metabolic reprogramming is dependent on Lin28b and that LIP enhances Lin28b expression through transcriptional repression of the let-7 microRNA family. Transgenic mice overexpressing LIP have reduced levels of let-7 in bone marrow, skin and spleen, which is associated with induction of Lin28b and hyperplasia. This study establishes LIP as a regulator of the let-7/Lin28b regulatory circuitry and we hypothesize that the LIP-controlled let-7/Lin28b regulation is involved in the de-regulation of tissue homeostasis and tumourigenesis.
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Project description:Deubiquitylases (DUBs) remove ubiquitin from proteins. In the context of cancer, their inhibition can induce the degradation of oncoproteins, that may otherwise be “undruggable”. Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome and high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies. However, the role of DUBs in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B subsequent to LIN28B phosphorylation. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. Binding of LIN28B at G1/S activates OTUD6B, which otherwise remains in a catalytically inactive state. As a consequence, stabilized LIN28B drives MYC expression via inhibition of let7 microRNAs, which in turn allows for a rapid transition of MM cells from G1 to S phase. Analyses of primary MM patient samples reveal a positive correlation of OTUDB6B expression with poor outcome, high MYC expression and MYC target gene induction, suggesting that high MYC levels in MM result from an activation of the OTUD6B-LIN28B nexus. Together, we here specify phosphorylation and cell cycle-dependent substrate binding as a means by which OTUD6B becomes activated to drive the G1/S transition via the LIN28B-MYC axis and nominate OTUD6B and LIN28B as actionable vulnerabilities in MM.
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Project description:Human neurodevelopment requires differentiating neurons to establish large networks of connections in a highly stereotyped manner. Neuronal differentiation in particular, requires RNA-binding proteins to spatiotemporally regulate thousands of different mRNAs. Yet, how these proteins precisely relate to neuronal development and coordinate the expression of functionally coherent genes in a cell type specific manner is only partially understood. To address this, we sought to understand how the paradigmatic RNA-binding protein IMP1/IGF2BP1, an essential developmental factor, selects and regulates its RNA targets transcriptome-wide during the differentiation of human neurons. We used a combination of systemic and molecular analyses to show that IMP1 directly binds to and regulates the expression of a large set of mRNAs that govern microtubule assembly, an essential process and a key driver of neuronal differentiation. We also show that m6A methylation during the transition from neural precursors to neurons drives both the selection of IMP1 mRNA targets and their translation potential. Our findings establish m6A methylation as a key mechanism coordinating the regulatory action of IMP1 on human neuronal architecture.
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