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LncRNA LINC00839 promotes colorectal cancer progression by RUVBL1/Tip60-NRF1 signaling pathway

ABSTRACT: Purpose: we focused on the biological roles and mechanism of the lncRNA LINC00839 in CRC. Methods: In situ hybridization (ISH), and quantitative real-time PCR (qPCR) were used to detect the expression of LINC00839 in paired CRC specimen. Biological function of LINC00839 was determined in vitro and in vivo. Western blot, bioinformatics analysis, RNA pull-down, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation assays (ChIP) were performed to identify the mechanisms underlying the functions of LINC00839 in CRC. Results: We found that LINC00839 was located in the nucleus of CRC cells and that LINC00839 was upregulated in CRC. High expression of LINC00839 was associated with poor outcome in CRC patients. Functionally, upregulation of LINC00839 promoted CRC cell proliferation, invasion, and metastasis in vitro and in vivo. Mechanistic investigations revealed that LINC00839 can promote the acetylation of histones H4K5 and H4K8 at the promoter of NRF1 after recruiting the RUVBL1/Tip60 complex, thereby upregulating the expression of NRF1. Subsequently, NRF1 served as an activator in mitochondrial metabolism and biogenesis, which, in turn, promoted CRC progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197706 | GEO | 2022/08/30

REPOSITORIES: GEO

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Project description:Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylationsensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions. DNase-seq (2 replicates) in mouse embryonic stem cells with (WT) and without DNA methylation (DNMT TKO). RNA-seq (3 replicates) in WT and DNMT TKO cells and in DNMT TKO cells after treatment with control siRNA or siRNA targeting Nrf1. H3K27ac ChIP-seq (2 replicates) in WT and DNMT TKO cells. NRF1 ChIP-seq (2 replicates) in WT and DNMT TKO cells, in WT upon culture in different conditions (adaptation to 2i and back to serum), upon transient overexpression of NRF1 and after differentiation into neuronal progenitor cells (NP). Whole-genome bisulfite sequencing in DNMT TKO cells and in WT upon culture in different conditions (adaptation to 2i and back to serum). NRF1 ChIP-seq (2 replicates) in human HMEC and HCC1954 cells.

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LncRNA LINC00839 promotes colorectal cancer progression by RUVBL1/Tip60-NRF1 signaling pathway

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