HBL1 Is a Human Long Noncoding RNA that Modulates Cardiomyocyte Development from Pluripotent Stem Cells by Counteracting MIR1

Liu, Juli; Li, Yang; Lin, Boqiang; Sangbong, Yi; Yang, Liu

doi:10.1016/j.devcel.2017.10.026

Cited by 21 publications

(35 citation statements)

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“…Because of their cancer-specific expression pattern, lncRNAs carry tremendous potential for novel targeted treatment approaches 15 16. Although the number of lncRNAs, including the primate-specific/human-specific ones,17–22 probably will surpass the number of coding genes,23 24 at present time only few of the former are proved to be involved in cancers,25 as the main focus of the translational research nowadays is on genes (coding or non-coding) highly conserved in evolution 8 13 26. Recently, we reported that multiple genomic non-coding loci harbouring human-specific/primate-specific motifs, named pyknons27, are differentially transcribed between CRC and normal colon and between poor versus good prognosis chronic lymphocytic leukaemia (CLL), and the expression levels correlate with patients’ overall survival 25.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer

Pichler

Rodríguez-Aguayo

Nam

et al. 2020

Gut

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ObjectiveTo investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.DesignFLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.ResultsFLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.ConclusionsBased on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.

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Section: Introductionmentioning

confidence: 99%

Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer

Pichler

Rodríguez-Aguayo

Nam

et al. 2020

Gut

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“…LncRNAs are distributed in both the nucleus and cytoplasm and regulate intracellular signaling pathways via different mechanisms, including chromatin modification, gene transcription regulation, and competing endogenous RNAs (ceRNAs) [48]. Among these, ceRNAs have a potentially important role in cardiac-related diseases [49,50]. Recent studies revealed that cardiac hypertrophy-related factor regulated cardiac hypertrophy by targeting miR-489.…”

Section: Discussionmentioning

confidence: 99%

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

2020

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Aims: Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIFpretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. Methods and results: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosome MIF), and delivered to cardiomyocytes subjected to H 2 O 2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. Exosome MIF protected cardiomyocytes from H 2 O 2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosome MIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosome MIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosome MIF inhibited H 2 O 2-induced apoptosis through modulating oxidative stress. Conclusions: Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosome MIF in protecting cardiomyocytes from apoptosis.

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“…17 In contrast, a human lncRNA Heartbreak is a negative regulator of cardiomyocyte differentiation and the overexpression of Heartbreak represses cardiomyocyte differentiation from hiPSCs by counteracting MIR1. 16 In summary, our findings provide evidence for the involvement of lncRNA GATA6-AS1 in cardiomyocyte differentiation as well as potential insights in the molecular regulation of cardiogenesis by linking the expression of GATA6-AS1 with GATA6 and the Wnt signaling.…”

Section: Discussionmentioning

confidence: 58%

A long non‐coding RNA GATA6‐AS1 adjacent to GATA6 is required for cardiomyocyte differentiation from human pluripotent stem cells

Jha

Liu

et al. 2020

The FASEB Journal

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Long noncoding RNAs (lncRNAs) are crucial in many cellular processes, yet relatively few have been shown to regulate human cardiomyocyte differentiation. Here, we demonstrate an essential role of GATA6 antisense RNA 1 (GATA6-AS1) in cardiomyocyte differentiation from human pluripotent stem cells (hPSCs). GATA6-AS1 is adjacent to cardiac transcription factor GATA6. We found that GATA6-AS1 was nuclear-localized and transiently upregulated along with GATA6 during the early stage of cardiomyocyte differentiation. The knockdown of GATA6-AS1 did not affect undifferentiated cell pluripotency but inhibited cardiomyocyte differentiation, as indicated by no or few beating cardiomyocytes and reduced expression of cardiomyocyte-specific proteins. Upon cardiac induction, the knockdown of GATA6-AS1 decreased GATA6 expression, altered Wnt-signaling gene expression, and reduced mesoderm development. Further characterization of the intergenic region between genomic regions of GATA6-AS1 and GATA6 indicated that the expression of GATA6-AS1 and GATA6 were regulated by a bidirectional promoter within the intergenic region. Consistently, GATA6-AS1 and GATA6 were co-expressed in several human tissues including the heart, similar to the mirror expression pattern of GATA6-AS1 and GATA6 during cardiomyocyte differentiation. Overall, these findings reveal a previously unrecognized and functional role of lncRNA GATA6-AS1 in controlling human cardiomyocyte differentiation.

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HBL1 Is a Human Long Noncoding RNA that Modulates Cardiomyocyte Development from Pluripotent Stem Cells by Counteracting MIR1

Cited by 21 publications

References 0 publications

Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer

Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

A long non‐coding RNA GATA6‐AS1 adjacent to GATA6 is required for cardiomyocyte differentiation from human pluripotent stem cells

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