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Deregulated high expression of NEAT1 lncRNA in multiple myeloma is unrelated to molecular features and clinical outcome

ABSTRACT: Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells, whose pathogenesis remains largely unknown. Long ncRNAs (lncRNAs) are a large class of non-protein-coding RNA, involved in many physiological cellular and genomic processes as well as in carcinogenesis, cancer metastasis and invasion. The biological role and therapeutic potential of lncRNAs in MM are still to be explored. Herein, we investigated the nuclear paraspeckle assembly transcript 1 (NEAT1) in the context of plasma cell dyscrasia, in a cohort of 50 MM and 15 plasma cell leukemia samples. Array expression data indicated that NEAT1 was upregulated in tumor samples compared to four healthy controls. Moreover, in MM patients, NEAT1 was globally overexpressed irrespectively of molecular characteristic, as further supported by Q-RT-PCR validation and by RNA sequencing data in a representative subgroup of cases. The functional annotation of genes and the lncRNAs transcriptional signature associated with NEAT1 expression indicated the modulation of DNA repair and metabolism, dynein interaction and unfolded protein response pathways. We tested NEAT1 clinical relevance in a retrospective proprietary dataset including 55 MM and in the large TT2/TT3 trials cohort from the University of Arkansas encompassing more than 550 patients; in both cases, NEAT1 overexpression was not correlated with patient’s prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116294 | GEO | 2019/06/18

REPOSITORIES: GEO

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Project description:Long noncoding RNAs (lncRNAs) are important regulators of chromatin; however, the mechanistic roles for many lncRNAs are poorly understood in part because their direct interactions with genomic loci and proteins are difficult to assess. We used CHART-seq to map the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1, which localize within the nucleus to paraspeckles and nuclear speckles, respectively. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs. Protein mass spectrometry analysis of CHART-enriched material (CHART-MS) identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation affects the localization of NEAT1 to active chromatin sites, implying that DNA sequence itself does not target NEAT1 to chromatin and that localization responds to cues involved in the transcription process. Paired-end CHART-seq was performed for a single replicate of each capture oligonucleotide in untreated MCF-7 cells to establish binding sites of these RNAs, for a total of 6 samples. To investigate the effects of transcriptional inhibition and E2 stimulation on the localization of these RNAs, we performed paired-end CHART-seq with each capture oligonucleotide for two biological replicates of flavopiridol- and vehicle (DMSO)-treated MCF-7 cells and for two biological replicates of E2- and vehicle (ethanol)-treated MCF-7 cells. To establish the overlap of NEAT1 and MALAT1 binding sites with a known component of paraspeckles (NEAT1-containing subnuclear body), we performed paired-end ChIP-seq for the paraspeckle component PSF in MCF-7 cells, as well as a single-end biological replicate.

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Deregulated high expression of NEAT1 lncRNA in multiple myeloma is unrelated to molecular features and clinical outcome

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