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A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells.

ABSTRACT: Long noncoding RNAs (lncRNAs) have emerged as important components of gene regulatory network in embryonic stem cells (ESCs). However, the function and molecular mechanism of lncRNAs are still largely unknown. Here we identifies Trincr1 (TRIM71 interacting long noncoding RNA 1) lncRNA that regulates the FGF/ERK signaling and self-renewal of ESCs. Trincr1 is exported by THOC complex to cytoplasm where it binds and represses TRIM71, leading to the downregulation of SHCBP1 protein. Knocking out Trincr1 leads to the upregulation of phosphorylated ERK and ERK pathway target genes and the decrease of ESC self-renewal, while knocking down Trim71 completely rescues the defects of Trincr1 knockout. Furthermore, ectopic expression of Trincr1 represses FGF/ERK signaling and the self-renewal of neural progenitor cells (NPCs). Together, this study highlights lncRNA as an important player in cell signaling network to coordinate cell fate specification.

SUBMITTER: Li YP

PROVIDER: S-EPMC6433952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells

Project description:Long noncoding RNAs (lncRNAs) have emerged as important components of gene regulatory network in embryonic stem cells (ESCs). However, the function and molecular mechanism of lncRNAs are still largely unknown. Here we identified Trincr1 (TRIM71 interacting long noncoding RNA 1) lncRNA that regulates the FGF/ERK signaling and self-renewal of ESCs. Trincr1 is exported by THOC complex to cytoplasm where it binds and represses TRIM71, leading to the downregulation of SHCBP1 protein. Knocking out Trincr1 led to the upregulation of phosphorylated ERK and ERK pathway target genes and the decrease of ESC self-renewal, while knocking down Trim71 completely rescued the defects of Trincr1 knockout. Furthermore, ectopic expression of Trincr1 repressed FGF/ERK signaling and the self-renewal of neural progenitor cells. Together, this study reveals novel regulators in FGF/ERK signaling pathway and highlights lncRNA as an important player in cell signaling network to coordinate cell fate specification.

2019-01-23 | GSE125458 | GEO

A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells

Project description:A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells

| PRJNA516435 | ENA

Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells.

Project description:Signal transduction networks generate characteristic dynamic activities to process extracellular signals and guide cell fate decisions such as to divide or differentiate. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, only a few studies have addressed the dynamic activity of the FGF/ERK signaling network in pluripotent cells at high time resolution. Here, we use live cell sensors in wild-type and Fgf4-mutant mouse embryonic stem cells to measure dynamic ERK activity in single cells, for defined ligand concentrations and differentiation states. These sensors reveal pulses of ERK activity. Pulsing patterns are heterogeneous between individual cells. Consecutive pulse sequences occur more frequently than expected from simple stochastic models. Sequences become more prevalent with higher ligand concentration, but are rarer in more differentiated cells. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells. The resulting heterogeneous dynamic signaling activities add a new dimension to cellular heterogeneity that may be linked to divergent fate decisions in stem cell cultures.

| S-EPMC8918804 | biostudies-literature

Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells.

Project description:Many long noncoding RNA (lncRNA) species have been identified in mammalian cells, but the genomic origin and regulation of these molecules in individual cell types is poorly understood. We have generated catalogs of lncRNA species expressed in human and murine embryonic stem cells and mapped their genomic origin. A surprisingly large fraction of these transcripts (>60%) originate from divergent transcription at promoters of active protein-coding genes. The divergently transcribed lncRNA/mRNA gene pairs exhibit coordinated changes in transcription when embryonic stem cells are differentiated into endoderm. Our results reveal that transcription of most lncRNA genes is coordinated with transcription of protein-coding genes.

| S-EPMC3581948 | biostudies-literature

The long noncoding RNA lncR492 inhibits neural differentiation of murine embryonic stem cells.

Project description:RNA interference (RNAi) screens have been shown to be valuable to study embryonic stem cell (ESC) self-renewal and they have been successfully applied to identify coding as well as noncoding genes required for maintaining pluripotency. Here, we used an RNAi library targeting >640 long noncoding RNAs (lncRNA) to probe for their role in early cell differentiation. Utilizing a Sox1-GFP ESC reporter cell line, we identified the lncRNA lncR492 as lineage-specific inhibitor of neuroectodermal differentiation. Molecular characterization showed that lncR492 interacts with the mRNA binding protein HuR and facilitates its inhibitory function by activation of Wnt signaling. Thus, lncRNAs modulate the fate decision of pluripotent stem cells.

| S-EPMC5783419 | biostudies-literature

Long Noncoding RNA Moderates MicroRNA Activity to Maintain Self-Renewal in Embryonic Stem Cells.

Project description:Of the thousands of long noncoding RNAs expressed in embryonic stem cells (ESCs), few have known roles and fewer have been functionally implicated in the regulation of self-renewal and pluripotency, or the reprogramming of somatic cells to the pluripotent state. In ESCs, Cyrano is a stably expressed long intergenic noncoding RNA with no previously assigned role. We demonstrate that Cyrano contributes to ESC maintenance, as its depletion results in the loss of hallmarks of self-renewal. Delineation of Cyrano's network through transcriptomics revealed widespread effects on signaling pathways and gene expression networks that contribute to ESC maintenance. Cyrano shares unique sequence complementarity with the differentiation-associated microRNA, mir-7, and mir-7 overexpression reduces expression of a key self-renewal factor to a similar extent as Cyrano knockdown. This suggests that Cyrano functions to restrain the action of mir-7. Altogether, we provide a view into the multifaceted function of Cyrano in ESC maintenance.

| S-EPMC5511051 | biostudies-literature

Interactome determination of a Long Noncoding RNA implicated in Embryonic Stem Cell Self-Renewal.

Project description:Long noncoding RNAs (lncRNAs) constitute a significant fraction of mammalian transcriptomes and they have emerged as intricate regulators of many biological processes. Their broad capacity to adopt diverse structures facilitates their involvement in the transcriptional, translational and signaling processes that are central to embryonic stem (ES) cell self-renewal and pluripotency. While lncRNAs have been implicated in ES cell maintenance, detailed analyses of those that show significant expression in ES cells is largely absent. Moreover, cooperative molecular relationships that facilitate lncRNA action are poorly understood. Cyrano is a developmentally important lncRNA, and in ES cells, it supports gene expression network maintenance, cell adhesion and cell survival. We have interrogated the interactome of Cyrano to identify protein partners and find that Cyrano is involved in multiple protein networks. We identify a developmentally important cell-signaling hub and find STAT3 as a candidate through which Cyrano can function to reinforce self-renewal of ES cells. Based on commonalities between ES cells and cancer cells, we postulate such functional interactions may support cell proliferation, cell identity and adhesion characteristics in rapidly proliferating cell types. The interactome data will therefore provide a resource for further investigations into interactions that regulate Cyrano or mediate its function.

| S-EPMC6279841 | biostudies-literature

The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells.

Project description:While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations.

| S-EPMC4388801 | biostudies-literature

Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer.

Project description:Long noncoding RNAs (lncRNAs) have received increased attention as a new class of functional regulators involved in human carcinogenesis. HOXA cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster that regulates gene expression at a transcription level. HOXA-AS2 is previously found to be overexpressed in gastric cancer (GC) and promotes GC cells proliferation. However, its potential role and molecular mechanism in colorectal cancer (CRC) are not known. Here, we identified that HOXA-AS2 is significantly upregulated in CRC tissue. In addition, increased HOXA-AS2 expression is associated with a larger tumor size and an advanced pathological stage in CRC patients. HOXA-AS2 knockdown significantly suppressed proliferation by blocking the G1/S transition and caused apoptosis of CRC cells in vitro and in vivo. The mechanistic investigations showed that HOXA-AS2 could interact with EZH2 (enhancer of zeste homolog 2), LSD1 (lysine specific demethylase 1) and recruit them to p21 (CDKN1A), KLF2 promoter regions to repress their transcription. Furthermore, the rescue experiments demonstrated that HOXA-AS2 oncogenic function is partly through regulating p21. In conclusion, our data suggest that HOXA-AS2 may function as an oncogene by modulating the multiple genes expression involved in CRC proliferation, and also provides a potential target for CRC therapy.

| S-EPMC5294247 | biostudies-literature

Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.

Project description:The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1, Dlx4, Gata6, and Ecsit. We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as, which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.

| S-EPMC2527704 | biostudies-literature

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