lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators

Blank-Giwojna, Alena; Postepska‐Igielska, Anna; Grummt, Ingrid

doi:10.1016/j.celrep.2019.02.059

Cited by 85 publications

(53 citation statements)

References 39 publications

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“…The ZnF710-aS1-202 transcript plays an important role in regulating ZnF710 expression. The effect of ZnF710-aS1-202 on rcc cells may be achieved through the ZnF710 protein (19,23,28). Therefore, further research is required to elucidate the mechanism by which ZnF710-aS1-202 downregulated ZnF710 mrna expression and upregulated ZnF710 protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…antisense lncrnas (aS lncrnas), a subclass of lncrnas, are transcribed from complex genetic loci on the opposite strands of sense protein-coding genes (13)(14)(15)(18)(19)(20). aS lncrnas may overlap exons and/or introns of their associated sense protein-coding transcripts to regulate epigenetic silencing, transcription and mrna stability by forming sense-antisense pairs (18)(19)(20)(21)(22)(23)(24). The genomic arrangement of aS lncrna genes also suggests that they may be involved in pathways that allow genes to regulate their own expression (23).…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of antisense long non‑coding RNA ZNF710‑AS1‑202 promotes cell proliferation and inhibits apoptosis of clear cell renal cell carcinoma via regulation of ZNF710 expression

Xie

Huang

et al. 2020

Mol Med Report

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antisense long non-coding rnas (aS lncrnas) have been increasingly recognized as important regulators of gene expression and have been found to play crucial roles in the development and progression of tumors. The present study explored the roles of aS lncrna ZnF710-aS1-202 in clear cell renal cell carcinoma (ccrcc). The expression levels of ZnF710-aS1-202 were detected in 46 human ccrcc tissues and 34 healthy adjacent renal tissues. The associations between the levels of ZnF710-aS1-202 expression and the clinicopathological features of the patients were evaluated by the χ 2 test. Gain-and loss-of-function experiments were performed to analyze the role of ZnF710-aS1-202 in ccrcc cell proliferation and survival in vitro. reverse transcription-quantitative Pcr and/or western blotting were employed to detect ZNF710-AS1-202, zinc finger protein 710 (ZNF710) and cyclin B1 expression. The cell counting Kit-8 and colony formation assays, as well as flow cytometry, were used to detect cell proliferation or apoptosis. The subcellular localization of ZNF710-AS1-202 was analyzed by RNA fluorescence in situ hybridization. The results revealed that ZnF710-aS1-202 was downregulated in human ccrcc tissues and was associated with the pathological grade, tumor size, local invasion and TnM stage, but not with lymph node metastasis or distant metastasis. However, ZnF710-aS1-202 overexpression promoted the proliferation of rcc cells and inhibited apoptosis. opposite results were observed when ZnF710-aS1-202 was knocked down by small interfering rna. Furthermore, ZnF710-aS1-202, which was mainly expressed in the cytoplasm of rcc cells, regulated ZnF710 mrna and protein expression in opposing manners. in conclusion, the present study revealed that ZnF710-aS1-202 and ZnF710 may serve as promising therapeutic targets for ccrcc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of antisense long non‑coding RNA ZNF710‑AS1‑202 promotes cell proliferation and inhibits apoptosis of clear cell renal cell carcinoma via regulation of ZNF710 expression

Xie

Huang

et al. 2020

Mol Med Report

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“…The DNA-ncRNA hybrids of the R-loops might be an excellent option to tether HMGA2 to specific promoters. Similarly, triple-helical RNA-DNA-DNA structures (triplex) at enhancers and promoters allow lncRNAs to recruit protein complexes to specific genomic regions and regulate gene expression (Blank-Giwojna et al, 2019;Kuo et al, 2019). Interestingly, Summer and colleagues demonstrated in a seminal work that HMGA2 binds and efficiently cleaves ssDNA containing abasic sites in vitro (Summer et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation

Dobersch

Rubio

Singh

et al. 2020

Preprint

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In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X.Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure the integrity of the genome. RESULTSHMGA2 is required for pH2A.X deposition at transcription start sites.We have previously reported that HMGA2-mediated transcription requires phosphorylation of the histone variant H2A.X at S139, which in turn is catalyzed by the protein kinase ATM (Singh et al., 2015). To further dissect this mechanism of transcription initiation, we decided first to determine the effect of Hmga2-knockout (KO) on genome wide levels of pH2A.X. We performed next generation sequencing (NGS) after chromatin immunoprecipitation (ChIP-seq;Figures 1 and S1A) using pH2A.X-specific antibodies and chromatin isolated from mouse embryonic fibroblasts (MEF) from wild-type (WT = Hmga2+/+) and Hmga2-deficient (Hmga2-KO = Hmga2−/−) embryos. The analysis of these ChIP-seq results using the UCSC Known Genes dataset (Hsu et al., 2006) revealed that pH2A.X is specifically enriched at transcription start sites (TSS) of genes in an Hmga2-dependent manner ( Figure 1A), seeing as Hmga2-KO significantly reduced pH2A.X levels. A zoom into the -750 to +750 base pair (bp) region relative to the TSS ( Figure 1B) revealed that pH2A.X levels significantly peaked at the TSS (-250 to +250 bp) in Hmga2+/+ MEF. Further, the genes were ranked based on pH2A.X levels at the TSS (Table S1) and the results were visualized as heat maps ( Figure 1C). From the top 15% of the genes with high pH2A.X levels at TSS (further referred as top 15% candidates), we selected Gata6 (GATA binding protein 6), Mtor (mechanistic target of rapamycin kinase) and Igf1 (insulin like growth factor 1) for further single gene analysis. Explanatory for these gene selection, we have previously reported Gata6 as direct target gene of HMGA2 Singh et al., 2015), KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment based analysis of the top 15% candidates showed significant enrichment of genes related to the mammalian target of rapamycin (mTOR) signaling pathway ( F...

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“…This work highlighted the relevance of these low copy number transcripts in the modulation of the transcriptional gene silencing; the same strategy was also efficiently applied to interfere with a promoter-associated lncRNA of the MYC gene, leading to profound inhibition of the development of prostate tumor xenografts [37,79]. Another evidence of the potential relevance of targeting pancRNAs in cancer therapy comes from the work performed by the laboratory of Dr. Grummt [44,80]. Transfection of a short synthetic RNA comprising the triplex-forming region of the pancRNAs Khps1 led to impaired cell migration, invasion, and clonogenicity of cancer cells.…”

Section: Therapeutic Targeting: Lessons From Pancrnasmentioning

confidence: 95%

“…Transfection of a short synthetic RNA comprising the triplex-forming region of the pancRNAs Khps1 led to impaired cell migration, invasion, and clonogenicity of cancer cells. As mentioned above, Khps1 is synthesized in antisense orientation to the proto-oncogene SPHK1 and is required for the activation of SPHK1 transcription by establishing a transcription-permissive chromatin structure and by increasing CBP/p300 occupancy and H3K27 acetylation to ensure E2F1 binding [44,80]. The discovery of this regulatory loop not only suggests the potential of using the pancRNA Khps1 as a biomarker but also represents a promising step toward therapeutic intervention.…”

Section: Therapeutic Targeting: Lessons From Pancrnasmentioning

confidence: 99%

Emerging Contribution of PancRNAs in Cancer

Neri

Palombo

Paronetto

2020

Cancers

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“Cancer” includes a heterogeneous group of diseases characterized by abnormal growth beyond natural boundaries. Neoplastic transformation of cells is orchestrated by multiple molecular players, including oncogenic transcription factors, epigenetic modifiers, RNA binding proteins, and coding and noncoding transcripts. The use of computational methods for global and quantitative analysis of RNA processing regulation provides new insights into the genomic and epigenomic features of the cancer transcriptome. In particular, noncoding RNAs are emerging as key molecular players in oncogenesis. Among them, the promoter-associated noncoding RNAs (pancRNAs) are noncoding transcripts acting in cis to regulate their host genes, including tumor suppressors and oncogenes. In this review, we will illustrate the role played by pancRNAs in cancer biology and will discuss the latest findings that connect pancRNAs with cancer risk and progression. The molecular mechanisms involved in the function of pancRNAs may open the path to novel therapeutic opportunities, thus expanding the repertoire of targets to be tested as anticancer agents in the near future.

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lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators

Cited by 85 publications

References 39 publications

Overexpression of antisense long non‑coding RNA ZNF710‑AS1‑202 promotes cell proliferation and inhibits apoptosis of clear cell renal cell carcinoma via regulation of ZNF710 expression

Overexpression of antisense long non‑coding RNA ZNF710‑AS1‑202 promotes cell proliferation and inhibits apoptosis of clear cell renal cell carcinoma via regulation of ZNF710 expression

Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation

Emerging Contribution of PancRNAs in Cancer

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