IMP1-interactive lncRNA regulates human endoderm differentiation via stabilizing WNT targets
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ABSTRACT:
PROVIDER: PRJNA779086 | ENA |
REPOSITORIES: ENA
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Project description:Long noncoding RNAs (lncRNAs) have been shown to play important roles in diverse biological process, including embryonic development and cell differentiation. Extensive studies have revealed the function and mechanism of those lncRNAs adjacent to protein-coding genes (PCGs), but there are relatively fewer reports about the lncRNAs within gene desert, particularly in human early germ layer differentiation. Here based on transcriptome analysis during human definitive endoderm (DE) differentiation, we identified a “desert” lncRNA named CTD-2501M5.1, a cytoplasm-located transcript with no protein-coding gene nearby within the 50 kb genomic region, highly expressed in human definitive endoderm. Depletion of CTD-2501M5.1 by either shRNA or promoter deletion could cause the deficiency of DE differentiation from human pluripotent stem cells (PSCs). The biochemical analysis showed that CTD-2501M5.1 functionally interacted with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1, also named IMP1), which is necessary for endoderm differentiation demonstrated by loss-of-function assay. We further found depletion of CTD-2501M5.1 could result in reduced WNT signaling activities. More importantly, manipulating WNT activity by chemicals could rescue the phenotype of DE deficiency due to the depletion of CTD-2501M5.1 or IMP1. Mechanistically, CTD-2501M5.1 facilitated the interaction between IMP1 and FZD5 mRNA, stabilizing FZD5 which is required for WNT signaling activation and DE differentiation. Ultimately, our study not only revealed the biological function of a novel desert lncRNA CTD-2501M5.1 in human DE differentiation, but also underlined lncRNA-mediated mRNA stability regulation via IMP1.
2023-03-30 | GSE188501 | GEO
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.
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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:We compared a transcriptome of hESC line VUB04 which has a low differentiation propensity towards definitive endoderm with transcriptomes of control hESC lines at the undifferentiated stage and after the 24-hour differentiation towards mesendoderm. The results showed that endogenous suppression of WNT signalling in VUB04 results in an inefficient switch from self-renewal to commitment during the definitive endoderm differentiation. Subsequenlty, we demonstrated that this differentiation disruption can be overcome by increasing the WNT stimulation or by inhibiting the PI3K/AKT signalling at the onset of differentiation.
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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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