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Analysis of LARP6 impact on RNA localisation to cell protrusions of Glioblastoma cells

ABSTRACT: LARP6 is a conserved RNA-binding domain that regulates the localisation of Ribosomal Protein mRNAs to the protrusions of mesenchymal-like cells. Our results had revealed that in addition to its folded La-module RNA binding domain, LARP6 makes direct contacts with its RNA targets via its disordered N-terminal region, which precedes the La-module. To assess the contribution of this region to the regulation of RNA localisation by LARP6, we carried out a spatial transcriptomics analysis of U-87 MG Glioblastoma cells, treated with scrambled control vs LARP6 3'UTR targeting siRNAs, with or without rescuing the LARP6 expression using a doxycycline-inducible full-legth or delta N-terminal mutant of LARP6. The cells were subjected to siRNA knockdown for 72hrs, before being seeded on 3um transwell filters and allowed to protrude through the pores for 90 mins. The protrusions and cell-bodies on opposite sides of the filter were isolateed, with total RNA extracted and subjected to RNA-sequencing using Lexogen QUANTSEQ 3' mRNA sequencing library preparation. Three independent biological replicates of each experiment were performed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316154 | GEO | 2026/01/22

REPOSITORIES: GEO

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TMT quantitative proteomics of a) protrusions and cells bodies of a panel of cell lines, b) protrusions and cells bodies of MDA-MB231 cells collected after 1 h, 2 h, 4 h, 8 h post- induction of protrusions, c) non-transfected (nt) or LARP6 siRNAs MDA-MB231 cells grown on either close or open collagen coated transwells and d) protrusions and cells bodies of a panel of breast cell lines.

Project description:Translation of Ribosomal Protein coding mRNAs (RP-mRNAs) constitutes a key step in regulation of ribosome biogenesis in human cells, but the exact mechanisms which modulate RP-mRNAs translation under various cellular and environmental conditions remain poorly understood. Here we show that the subcellular localisation of RP-mRNAs acts as a key regulator of their translation in mesenchymal-like migratory cells. As cells invade into their surroundings, RP-mRNAs localise to the actin-rich protrusions at the front of the cells. This localisation is mediated by La related protein-6 (LARP6), an RNA Binding Protein (RBP) that is enriched in protrusions. Importantly, translation initiation and elongation factors are also enriched in protrusions. LARP6 dependent localisation of RP-mRNAs enhances their translation, leading to up-regulation of ribosome biogenesis and increased overall protein synthesis. In breast carcinomas, enhanced expression of LARP6 is associated with Epithelial to Mesenchymal Transition (EMT), and can be therapeutically targeted by a small molecule inhibitor which interferes with LARP6 RNA binding. These findings reveal an RNA localisation based post-transcriptional mechanism that governs ribosome biogenesis in migratory cells, and implicate a role for this process in cancer progression downstream of EMT.

2021-09-08 | PXD015808 | Pride

QUANTSEQ 3' sequencing of protrusions and cell bodies of control (NT) or LARP6 siRNA (LARP6 KD) transfected MDA-MB231 breast cancer cells

Project description:To assess how LARP6 affects mRNA localisation to cell-protrusions, we transfected MDA-MB231 cells with either non-targeting control siRNA or LARP6 siRNA for 72 hrs, before fractionating the cells into protrusion and cell-bodies, and analysed total RNA from each fraction via Lexogen QUANTSEQ FWD 3' mRNA sequencing. Protrusion induction was done for 2 hrs on 3 micron transwell filters (Corning). The experiment was performed twice using two independent batches of cells, and sequencing was carried out on an Illumina NextSeq 500 sequencer.

2020-10-30 | E-MTAB-9520 | biostudies-arrayexpress

3' mRNA-seq of protrusions and cell bodies of non-transfected (nt) or LARP6 siRNA transfected MDA-MB231 cells

Project description:3' mRNA-seq of protrusions and cell bodies of nt or LARP6 siRNA transfected MDA-MB231 cells. These data show that Ribosomal protein (RP) -mRNAs localization to cell protrusions is mediated by LARP6.

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Analysis of LARP6 impact on RNA localisation to cell protrusions of Glioblastoma cells

Project description:Analysis of LARP6 impact on RNA localisation to cell protrusions of Glioblastoma cells

| PRJNA1401729 | ENA

Cardiomyocyte-specific LARP6 overexpression prevents Angiotensin II-induced myocardial dysfunction and interstitial fibrosis

Project description:La ribonucleoprotein 6, Translational Regulator (LARP6), a multifunctional mRNA binding protein with well-described pro-fibrotic effects, increases type I collagen mRNA half-life, translation, and deposition in non-cardiac tissues. In the heart LARP6 is expressed in cardiomyocytes, not primarily involved in fibrosis, where its role is unknown. To investigate the role of cardiomyocyte-derived LARP6 on cardiac function and remodeling, we generated a cardiomyocyte-specific LARP6 overexpressing transgenic mouse model (LARP6-Tg). Baseline longitudinal studies up to 10 months of age revealed that constitutive overexpression of LARP6 had no significant effect on cardiac function or morphology despite inducing mild interstitial fibrosis versus wild-type littermates (WT). Subsequently, we hypothesized that cardiomyocyte-specific LARP6-Tg mice would exhibit exacerbated cardiac remodeling and dysfunction in response to hypertensive stress via angiotensin II (Ang II) infusion. Ang II (1000 ng/kg/min for 21 days) induced hypertension and cardiac hypertrophy in WT and LARP6-Tg mice of both sexes. Unexpectedly, Ang II-induced cardiac dysfunction was prevented in LARP6-Tg mice. Cardiac gene expression profiling predicted increased fibrosis and cardiomyocyte death in Ang II-treated WT mice and inhibition of cardiomyocyte death in Ang II-treated LARP6-Tg mice, versus saline-treated controls. Surprisingly, Ang II-induced interstitial fibrosis was reduced in LARP6-Tg mice and associated with attenuation of cardiomyocyte cell death and reduced myofibroblast activation. These data support a mild pro-fibrotic action of cardiomyocyte LARP6 in unstressed mice and, paradoxically, that LARP6 overexpression is sufficient to prevent Ang II-induced cardiac interstitial fibrosis and dysfunction. Sustained induction of LARP6 has therapeutic potential in hypertensive heart disease.

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QUANTSEQ 3' sequencing of protrusions and cell bodies of control (NT) or LARP6 siRNA (LARP6 KD) transfected MDA-MB231 breast cancer cells

Project description:QUANTSEQ 3' sequencing of protrusions and cell bodies of control (NT) or LARP6 siRNA (LARP6 KD) transfected MDA-MB231 breast cancer cells

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Identification of mRNAS enriched in endothelial cell protrusions

Project description:Deciphering the complex biology of cell migration is key to understand human-related disorders. During angiogenesis, endothelial cells engage in coordinated migration events to form new blood vessels from parental counterparts. However, while subcellular localisation of mRNAs and localised translation are fundamental steps between gene transcription and protein activity, whether local regulation of gene expression controls the complex morphogenetic process of angiogenesis has never been addressed. Here, we set out to investigate the cytoplasmic distribution of mRNAs in migratory endothelial cells. We isolated RNA from endothelial cell protrusions from their cell bodies and used RNA-sequencing to identify asymmetrically distributed transcripts. These studies identified a set of transcripts enriched in endothelial cell protrusions over cell bodies, which included classically protrusion-enriched mRNAs and other intriguing transcripts encoding proteins implicated in cell migration.

2020-09-07 | GSE133055 | GEO

LARP6 shapes the mRNA translation of fibrogenic genes [eCLIP]

Project description:Metabolic syndrome and excessive alcohol consumption result in liver injury and fibrosis, which is characterized by an increased collagen production by activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate collagen production. However, LARP6 expression and functionality as a regulator of fibrosis development in a disease relevant model remains elusive. By using snRNA-seq, we show that LARP6 and collagen-associated genes are upregulated mainly in HSCs of hepatic fibrosis patients. Moreover, LARP6 knockdown in isolated HSCs suppressed fibrogenic genes expression. By integrating eCLIP analysis and ribosome profiling in HSCs, we show that LARP6 interacts with mature mRNAs comprising over three hundred genes, including RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. Furthermore, LARP6 reduction attenuates fibrosis in human liver spheroids. Altogether, our results suggest that targeting LARP6 in human HSCs may provide new strategies for anti-fibrotic prevention and therapy.

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LARP6 shapes the mRNA translation of fibrogenic genes [RNA-seq]

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TMT analysis of LARP6 knockdown impact on protrusion induced changes in the proteome of MDA-MB231 cells

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