Long noncoding RNA lnc-LEMGC combines with DNA-PKcs to suppress gastric cancer metastasis
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ABSTRACT:
PROVIDER: PRJNA748266 | ENA |
REPOSITORIES: ENA
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Project description:Long non-coding RNAs (lncRNAs) play important roles in cancer development and progression; however, their contributions to gastric cancer metastasis remain largely unknown. By lncRNA microarray screening, our study showed that 10 lncRNAs are dysregulated in gastric cancer tissues with or without lymph node metastasis, of which lnc-LEMGC ranks as one of the most significantly downregulated lncRNAs. Lnc-LEMGC inhibited cell migration and invasion both in vitro and in vivo, by combining with protein DNA-PKcs. Importantly, nucleotides 1,300–1,800 of lnc-LEMGC prevented DNA-PKcs phosphorylation of serine 2056 and partially abrogated the effects of downstream effectors, transforming growth factor alpha, EGFR, Src kinase, paxillin, and focal adhesion kinase, in the epidermal growth factor receptor (EGFR) pathway. The results of this study extend our knowledge of lncRNA’s molecular mechanisms, in which lnc-LEMGC functions by directly suppressing the phosphorylation of its combined protein DNA-PKcs and inactivating the DNA-PKcs downstream EGFR signaling.
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Project description:DNA-PKcs suppress chromosome translocation in human cells
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Project description:DNA-PKcs is a crucial component of the non-homologous end joining (NHEJ) repair machinery. To investigate its function in human cell lines, we conducted a study using K562 and HEK293T cell lines. We introduced twinned DNA double-strand breaks (DSBs) or genome-wide DSBs into these cell lines via nucleofection and transfection, respectively. Subsequently, we employed high-throughput genome translocation sequencing (HTGTS) to capture the translocation events (i.e., ligation between "prey(s)" and "bait") and the rejoining events (i.e., direct repair within the "bait" locus) under different conditions, including with or without DNA-PKcs inhibition or deletion. We quantified the number of translocation events by normalizing them to the number of rejoining events, denoted as TL. Interestingly, DNA-PKcs inhibition led to an increase in TL, indicating a higher frequency of translocations. However, it is important to note that chromosomal translocations still predominantly relied on NHEJ despite DNA-PKcs inhibition. Furthermore, we observed that DNA-PKcs deletion resulted in an elevated utilization of microhomology in translocation formation. Nevertheless, NHEJ remained the primary mechanism driving translocation events.These findings provide valuable insights into the role of DNA-PKcs in the repair pathways involved in translocation events in human cell lines. The utilization of HTGTS allowed us to comprehensively analyze the effects of DNA-PKcs inhibition and deletion, shedding light on the interplay between NHEJ and alternative repair mechanisms in translocation formation.
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Project description:Long noncoding RNAs (lncRNAs) have emerged as integral regulators of physiology and disease, but specific roles of lncRNAs in bone disease remain largely unknown. Here, we show that lnc-ob1 regulates osteoblast activity and bone formation in mice by upregulating the osteogenic transcription factor Osterix. Expression of lnc-ob1 is enriched in osteoblasts and upregulated during osteoblastogenesis. We demonstrate that osteoblast-specific knock-in of lnc-ob1 enhances bone formation and increases bone mass. Pharmacological overexpression of lnc-ob1 specifically in osteoblasts confers resistance to ovariectomy-induced osteoporosis in mice. In humans, expression of the homologue, lnc-OB1, decreases with age in osteoblasts of patients with osteoporosis. Mechanistically, lnc-ob1 upregulates the expression of Osterix in mouse and human osteoblasts, probably via inhibition of H3K27me3 methylation. Our data indicate that lnc-OB1 regulates bone formation and might be a drug target for the treatment of osteoporosis.
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Project description:Recent studies have indicated important roles for long noncoding RNAs (lncRNAs) as potential essential regulators of myogenesis and adult skeletal muscle regeneration. However, in vivo, the role and mechanism of lncRNAs in myogenic differentiation of adult skeletal muscle stem cells (MuSCs) and myogenesis are still largely unknown. Here, we identified a skeletal muscle specific-enriched lncRNA (myogenesis-associated lncRNA, short for lnc-mg). In vivo, skeletal muscle conditional knockout of lnc-mg resulted in muscle atrophy and the loss of muscular endurance during exercise. Alternatively, skeletal muscle-specific overexpression of lnc-mg promoted muscle hypertrophy in mice. In vitro analyses of primary skeletal muscle cells isolated from mice showed that expression of lnc-mg was increased gradually during myogenic differentiation and overexpressed lnc-mg improved cell differentiation. Mechanistically, lnc-mg promoted myogenesis, by functioning as a competing endogenous RNA (ceRNA) for miR-125b to control protein abundance of Igf2. These findings identify lnc-mg as a novel and important noncoding regulator for muscle cell differentiation and skeletal muscle development. In order to test the hypothesis that lnc-mg may function as a ceRNA leading to the liberation of corresponding miRNA-targeted transcripts, microarrays were performed to detect miRNAs expression in lnc-mg overexpression and lnc-mg knockdown C2C12 cells.
2017-03-01 | GSE93277 | GEO
Project description:Two DNA repair pathways, non-homologous end joining (NHEJ) and alternative end joining (A-EJ), are involved in V(D)J recombination and chromosome translocation. Previous studies reported distinct repair mechanisms for chromosome translocation, with NHEJ predominantly involved in human and A-EJ in mice. NHEJ depends on DNA-PKcs, a critical partner in synapsis formation and downstream component activation. While DNA-PKcs inhibition promotes chromosome translocations harboring microhomologies in mice, its synonymous effect in human is not known. We find partial DNA-PKcs inhibition in human cell lines leads to increased genome-wide translocations composed mostly of direct joints, indicating the continued involvement of dampened NHEJ in these processes. In contrast, complete DNA-PKcs inhibition and genetic inhibition DNA-PKcs kinase domain substantially increased microhomology-mediated end joining (MMEJ), thus bridging the two different translocation mechanisms between human and mice. Similar to a previous study on Ku70 deletion, DNA-PKcs deletion in G1/G0-phase mouse pro-B cell lines, impair the recombination of RAG1/2-mediated DNA double-strand breaks (DSBs). This DNA-PKcs-deficient repair mechanism exhibited reduced V(D)J recombination efficiency, increased end resection, decreased polymerase-mediated insertions, loss of recombination fidelity and generated relatively higher rates of chromosome translocation as a consequence of dysregulated coding and signal end joining. Our study underscores DNA-PKcs in suppressing illegitimate chromosome rearrangement in both species.
2023-12-30 | GSE249453 | GEO
Project description:Recent studies have indicated important roles for long noncoding RNAs (lncRNAs) as potential essential regulators of myogenesis and adult skeletal muscle regeneration. However, in vivo, the role and mechanism of lncRNAs in myogenic differentiation of adult skeletal muscle stem cells (MuSCs) and myogenesis are still largely unknown. Here, we identified a skeletal muscle specific-enriched lncRNA (myogenesis-associated lncRNA, short for lnc-mg). In vivo, skeletal muscle conditional knockout of lnc-mg resulted in muscle atrophy and the loss of muscular endurance during exercise. Alternatively, skeletal muscle-specific overexpression of lnc-mg promoted muscle hypertrophy in mice. In vitro analyses of primary skeletal muscle cells isolated from mice showed that expression of lnc-mg was increased gradually during myogenic differentiation and overexpressed lnc-mg improved cell differentiation. Mechanistically, lnc-mg promoted myogenesis, by functioning as a competing endogenous RNA (ceRNA) for miR-125b to control protein abundance of Igf2. These findings identify lnc-mg as a novel and important noncoding regulator for muscle cell differentiation and skeletal muscle development. In order to identify functional lncRNAs correlating with myogenesis, microarrays were performed to detect the lncRNAs expression profile in undifferentiated MuSCs (GM, growth media/GM) ) and differentiated MuSCs (DM, differentiation media/DM).
2017-03-01 | GSE93276 | GEO
Project description:Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles such as tumorigenesis. Recent advances also suggest that this 'enemy within' may encode viral mimic to induce antiviral immune responses through viral sensors. Here, through whole genome RNA-seq we discovered a full-length ERV-derived long non-coding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), as a positive regulator of NF-κB signaling. Lnc-EPAV expression was rapidly up-regulated by viral RNA mimic or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. In turn, RELA promoted the transcription of lnc-EPAV to form a positive feedback loop. Transcriptome analysis of lnc-EPAV-silenced macrophages, combined with gain- and loss-of-function experiments, showed that lnc-EPAV was critical for induction of type I interferon (IFN) and inflammatory cytokine expression by RNA viruses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I IFNs, and consequently increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of RELA. The binding between ERV-derived RNAs and SFPQ also existed in human cells. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses.
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Project description:Long noncoding RNAs (lncRNA) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remains unknown. By RNA-seq analyses of 18 clinical samples and validated by RT-qPCR analyses of 72 clinical samples, we provide the first evidence in this report that 194 lncRNAs are differentially regulated by high-risk HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, induced by high-risk HPV infection was carefully analyzed because it is expressed from the same chr 15q26.1 region of FANCI gene encoding an important DNA repair factor. We found a mutual regulation of lnc-FANCI-2 and FANCI in cervical cancer cells and high-risk E6 and mainly E7 for this upregulation independent of p53 and pRb/E2F1. In HPV16-positive CaSki cells, lnc-FANCI-2, primarily in the cytoplasm in ~10 copies per cell, is transcribed from two alternative promoters and polyadenylated at two alternative poly(A) sites. Alternative RNA splicing of lnc-FANCI-2 transcripts leads to produce 14 detectable RNA isoforms. YY1 interacts with viral E7 and transactivates the transcription by binding to two YY1-binding motifs in the lnc-FANCI-2 promoter. Knockdown of either YY1 or E7 expression led to significant reduction of lnc-FANCI-2 expression. The 3’ untranslational region of YY-1 RNA contains a consensus seed match to miR-29a and is sensitive to miR-29a-mediated inhibition of YY1 expression. High-risk HPV infections were found to induce YY1 expression in HPV18-infected HFKs by reduction of host miR-29a expression. Together, our data have provided novel insights into mechanisms of how high-risk HPVs contribute to cervical carcinogenesis.
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