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The pan-cancer lncRNA PLANE regulates an alternative splicing program and promotes cancer pathogenesis [ONT]

ABSTRACT: Genomic amplification of the distal portion of chromosome 3q that encodes a number of oncogenic proteins is one of the most prevalent chromosomal deformities. Here we functionally characterise a non-protein product of this region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as transcriptional activation by E2F1. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. As such, PLANE promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172124 | GEO | 2021/04/16

REPOSITORIES: GEO

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The pan-cancer lncRNA PLANE regulates an alternative splicing program and promotes cancer pathogenesis

Project description:Genomic amplification of the distal portion of chromosome 3q that encodes a number of oncogenic proteins is one of the most prevalent chromosomal deformities. Here we functionally characterise a non-protein product of this region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as transcriptional activation by E2F1. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. As such, PLANE promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.

2020-11-27 | GSE162215 | GEO

The pan-cancer lncRNA PLANE regulates an alternative splicing program and promotes cancer pathogenesis [ONT]

Project description:The pan-cancer lncRNA PLANE regulates an alternative splicing program and promotes cancer pathogenesis [ONT]

| PRJNA722174 | ENA

Cell-type restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

Project description:Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44s splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial-splicing regulator that binds to the same cis-regulatory RNA elements and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program. RNAseq for control, hnRNPM siRNA treated lung metastatic LM2 clonal line, derived from the mesenchymal MDA-MB-231 cells

2014-06-03 | E-GEOD-57243 | biostudies-arrayexpress

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [RNA-seq]

Project description:RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

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LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [iCLIP]

2024-05-29 | GSE227048 | GEO

Effect of early-life plane of nutrition on the transcriptional profile of the hypothalamic arcuate nucleus region in heifer calves

Project description:The aim of this study was to examine alterations in the transcriptional profile of the arcuate nucleus region of the hypothalamus between heifer calves offered varying planes of nutrition during early life. Angus X Holstein-Friesian heifer calves (19 ± 5 days of age, BW: 51.2 ± 7.8 kg, mean ± SD) were offered a high (HP, n=14) or moderate plane of nutrition (MP, n=15) from 3 to 21 weeks of age to achieve a target growth rate of 1.2 kg/d and 0.5 kg/d, respectively. At 21 weeks of age, all calves were euthanized and the arcuate nucleus region of the hypothalamus of each calf recovered. RNA was extracted transcriptional profiles examined using RNAseq. Compared with calves on the moderate plane of nutrition, a High plane of nutrition altered the expression of 80 genes within the arucate nucleus. Functional analysis of differentially expressed genes revealed functions including organismal development, behaviour, endocrine system development and function, lipid metabolism, molecular transport, small molecule biochemistry, cellular development, cellular growth and proliferation, and nervous system development and function to be affected by early life plane of nutrition in the arucate nucleus of heifer calves.

2021-07-14 | GSE153498 | GEO

Effect of early-life plane of nutrition on the transcriptional profile of visceral adipose tissue in heifer calves

Project description:The aim of this study was to examine changes in the transcriptional profile of visceral adipose tissue in heifer calves offered varying planes of nutrition during the early life period. From approximately 3 weeks of age (19 ± 5 days of age) Angus X Holstein-Friesian heifer calves were offered either a high (HP, n=15) or moderate (MP, n=15) plane of nutrition to achieve target growth rates of 1.2 kg/d and 0.5 kg/d, respectively. After 18 weeks of differential feeding all calves were euthanized and visceral adipose tissue samples harvested from each calf. RNA was extracted and subsequently subjected to RNAseq analysis. A total of 1052 genes were identified as significantly differentially expressed between calves on the High plane of nutrition and those on the Moderate plane of nutrition. Biological pathway analysis revealed an enrichement from these genes for processes and pathways including Sirtuin signalling, oxidative phosphorylation and adipogenesis.

2021-05-12 | GSE158128 | GEO

Maternal Plane Of Nutrition During Late Gestation And Weaning Age Alter Offspring Transcriptome Profiles Of Longissimus Muscle In Angus × Simmental

Project description:We evaluated if a higher plane of maternal nutrition during late gestation and weaning age alters the offspring’s Longissimus muscle (LM) transcriptome. A microarray analysis was performed in LM samples of early (EW) and normal weaned (NW) Angus × Simmental calves born from cows that were grazing endophyte-infected tall fescue/red clover pastures with no supplement (low plane of nutrition (LPN)), or supplemented with 2.3 kg of dried distiller’s grains with solubles and soyhulls (70% DDGS/30% soyhulls) (medium plane of nutrition (MPN)) during the last 90 days of gestation. Biopsies were harvested at 78, 187 and 354 days of age. Bioinformatics analysis highlighted that offspring transcriptome did not respond markedly to cow plane of nutrition, resulting in only 13 differentially expressed genes. However, weaning age and a high-starch diet strongly impacted the transcriptome, especially the immediate activation of the lipogenic program in EW steers. In addition, between 78 and 187 days of age, these animals had an activation of the innate immune system due presumably to macrophage infiltration in intramuscular fat. Between 187 and 354 days of age (i.e. the fattening phase), NW steers had an activation of the lipogenic transcriptome machinery, while EW steers had a clear gene transcription inhibition. The latter appears to have occurred through the epigenetic control of histone acetylases, which were down-regulated. Higher cow plane of nutrition alone affected 35 genes in the LM of steers that underscore the presence of a mechanism of macrophage infiltration likely originating from localized oxidative stress as a result of increased levels of hypoplasia and hypertrophy in LM.

2015-02-03 | GSE65560 | GEO

Effect of early-life plane of nutrition on the transcriptional profile of the anterior pituitary gland in heifer calves

Project description:The aim of this study was to examine changes in the transcriptional profile of the anterior pituitary gland of heifer calves offered varying planes of nutrition during the early life period. From approximately 3 weeks of age (19 ± 5 days of age) Angus X Holstein-Friesian heifer calves were offered either a high (HP, n=13) or moderate (MP, n=15) plane of nutrition to achieve target growth rates of 1.2 kg/d and 0.5 kg/d, respectively. After 18 weeks of differential feeding all calves were euthanized and anterior pituitary tissue samples harvested from each calf. RNA was extracted and subsequently subjected to RNAseq analysis. A total of 195 genes were identified as significantly differentially expressed between calves on the High plane of nutrition and those on the Moderate plane of nutrition. Biological pathway analysis revealed an enrichement from these genes for processes and pathways related to growth and reproductive system development.

2024-07-04 | GSE230543 | GEO

Effect of early-life plane of nutrition on the transcriptional profile of the hypothalamus in heifer calves

Project description:The objective of this study was to examine changes in hypothalamic gene expression of heifer calves offered varying planes of nutrition during early life. Angus X Holstein-Friesian heifer calves (19 ± 5 days of age, BW: 51.2 ± 7.8 kg, mean ± SD) were offered a high (HP, n=14) or moderate plane of nutrition (MP, n=15) from 3 to 21 weeks of age to achieve a target growth rate of 1.2 kg/d and 0.5 kg/d, respectively. At 21 weeks of age, all calves were euthanized and the hypothalamus of each calf recovered. RNA was extracted and hypothalamic gene expression examined using RNAseq. Compared with calves on the moderate plane of nutrition, a HP of nutrition altered the expression of 39 transcripts in the hypothalamus. Biological pathway analysis revealed these differentially expressed genes to be involved in pathways including acute phase response signalling, STAT3 pathway, and tight junction signalling. Additionally, biological functions affected by early life plane of nutrition included cell-to-cell signalling and interaction, molecular transport, small molecule biochemistry, behaviour, nervous system development and function, nucleic acid metabolism, and cellular function and maintenance.

2021-07-14 | GSE153495 | GEO

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