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Identification of LARP1 targets in naive CD4 T cells [eCLIP]

ABSTRACT: We investigated the role of RNMT in T cells using an Rnmt conditional knockout mouse model. We report that the mRNA cap methyltransferase, RNMT, supports naïve T cell survival and activation-induced proliferation. We demonstrate that RNMT has gene-specific impacts in T cells, selectively regulating expression of terminal polypyrimidine tract (TOP) mRNAs which are targets of the m7G-cap binding protein LARP1. These LARP1 eCLIP experiments determine the RNA binding sites of LARP1 in naive CD4 T cells from Rnmt cKO and control mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE160325 | GEO | 2021/05/13

REPOSITORIES: GEO

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RNMT regulates the naïve CD4 T cell transcriptome

Project description:We investigated the role of RNMT in T cells using an Rnmt conditional knockout mouse model. We report that the mRNA cap methyltransferase, RNMT, supports naïve T cell survival and activation-induced proliferation. We demonstrate that RNMT has gene-specific impacts in T cells, selectively regulating expression of terminal polypyrimidine tract (TOP) mRNAs which are targets of the m7G-cap binding protein LARP1. These RNAseq experiments investigate the effect of Rnmt cKO on the naïve CD4 T cell transcriptome.

2021-05-13 | GSE160267 | GEO

RNMT regulates the activated CD4 T cell transcriptome and translatome [Ribo-Seq]

Project description:We investigated the role of RNMT in T cells using an Rnmt conditional knockout mouse model. We report that the mRNA cap methyltransferase, RNMT, supports naïve T cell survival and activation-induced proliferation. We demonstrate that RNMT has gene-specific impacts in T cells, selectively regulating expression of terminal polypyrimidine tract (TOP) mRNAs which are targets of the m7G-cap binding protein LARP1. These ribosome footprinting experiments investigate the effect of Rnmt cKO on the activated CD4 T cell transcriptome and translatome.

2021-05-13 | GSE160326 | GEO

GCN2 suppresses TOP mRNA translation via LARP1

Project description:La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine tract (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5’TOP motif, resulting in the displacement of the eIF4E complex from TOP mRNAs. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. GCN2 inhibits TOP mRNA translation via ATF4-dependent transcriptional induction of LARP1 mRNAs and GCN1-mediated recruitment of LARP1 to stalled ribosomes. We performed ATF4 ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.

2022-08-31 | GSE166590 | GEO

Psuedouridine sequencing rRNA in Rnmt cKO CD4 T cells

Project description:We investigated the role of RNMT in T cells using an Rnmt conditional knockout mouse model. We report that the mRNA cap methyltransferase, RNMT, supports naïve T cell survival and activation-induced proliferation. We demonstrate that RNMT has gene-specific impacts in T cells, selectively regulating expression of terminal polypyrimidine tract (TOP) mRNAs and small RNAs including snoRNAs. To deterine if had any effect on ribosomal RNA modification we carried out pseudoridine sequencing.

2021-05-13 | GSE165790 | GEO

Identification of LARP1 targets in naive CD4 T cells [eCLIP]

Project description:Identification of LARP1 targets in naive CD4 T cells [eCLIP]

| PRJNA672953 | ENA

The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction

Project description:The mammalian target of rapamycin (mTOR) is a pivotal kinase responsible for transducing cellular energy signals to regulate a host of metabolic processes including protein synthesis, which in turn regulate cell growth and proliferation. All aspects of mRNA life cycle are controlled by protein/RNA interactions and although several effectors of mTOR signalling have been identified to date, how mTOR re-sculptures the mRNA interactome is unknown. Here we characterise mTOR regulated RNA-binding proteins, identifying LARP1, whose binding to RNA increases upon mTOR inhibition. We identified over 3800 LARP1 bound mRNAs, which can be broken down into two groups, those constantly bound by LARP1, or mRNAs that increase their interaction following mTOR inhibition. LARP1 has been implicated in the control of TOP mRNA translation and importantly we observe a large number of TOP mRNAs increasing association with LARP1 upon mTOR inhibition. Regarding the regulation of LARP1, we show that LARP1 and PABP show coordinated differential mRNA binding after mTOR inhibition. Importantly we find that LARP1-PABP interaction is important for LARP1 mRNA binding and mutations in the DM15 domain of LARP1 do not perturb its RNA interaction. Lastly we show that mRNAs bound by LARP1 and PABP are translationally repressed, including mRNAs encoding proteins critical for cell growth and survival.

2020-12-11 | GSE142539 | GEO

mRNA cap methyltransferase, RNMT-RAM, promotes RNA pol II transcription

Project description:mRNA cap addition occurs early during RNA pol II transcription, facilitating pre-mRNA processing and translation. We report that the mammalian mRNA cap methyltransferase, RNMT-RAM, promotes RNA pol II transcription, independently of mRNA capping and translation. In cells, sub-lethal suppression of RNMT-RAM reduces RNA pol II occupancy, net mRNA synthesis and pre-mRNA levels. Conversely, expression of RNMT-RAM increases transcription independently of cap methyltransferase activity. In isolated nuclei, recombinant RNMT-RAM stimulates transcriptional output; this requires the RAM RNA-binding domain. RNMT-RAM interacts with nascent transcripts along their entire length and with transcription associated factors including RNA pol II subunits, SPT4, SPT6 and PAFc. Suppression of RNMT-RAM inhibits transcriptional markers including histone H2B K120 ubiquitination, H3 K4 and K36 methylation, RNA pol II S5 and S2 phosphorylation and PAFc recruitment. These findings suggest that multiple interactions between RNMT-RAM, RNA pol II factors and RNA along the transcription unit stimulate transcription.

2018-05-01 | GSE87767 | GEO

LARP1 senses free ribosomes to coordinate supply and demand of ribosomal proteins

Project description:Terminal oligopyrimidine motif-containing (TOP) mRNAs encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies implicate LARP1 in 40S- or 80S-ribosome complexes that repress and stabilize TOP mRNAs. However, a mechanistic understanding of how LARP1 and TOP mRNAs interact with ribosomes to coordinate TOP mRNA outcomes is lacking. Here, we show that LARP1 senses the cellular supply of ribosomes by directly binding non-translating 80S ribosomes. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the 40S mRNA channel and mutations at the LARP1-ribosome interface block formation of the 40S/80S-LARP1-TOP complexes. Free cytosolic ribosomes induce sequestration of TOP mRNAs in repressed 80S-LARP1-TOP complexes independent of alterations in mTOR signaling. Together, this work demonstrates a ribosome-sensing function of LARP1 that allows it to tune ribosome protein synthesis to the availability of free ribosomes.

2023-10-28 | GSE246077 | GEO

Transcriptomic analysis of WT and larp1 mutant 21 days old seedling at 20°C or following a heat stress (15 min at 38°C)

Project description:We report the identification of a heat-stress mediated mRNA decay in arabidopsis that is mediated by the XRN4 exonuclease and LARP1 RNA-binding protein. mRNA population in WT and larp1 mutant at 20C or 15 min at 38C

2014-03-28 | E-GEOD-51879 | biostudies-arrayexpress

LARP1 mRNP scaffolds mTORC1 to stimulate translation initiation of an essential class of mRNAs

Project description:The RNA biding protein, LARP1, has been proposed to function downstream of mTORC1 to positively regulate the translation of 5M-bM-^@M-^YTOP mRNAs such as ribosome protein (RP) mRNAs. However, its regulatory roles in mTORC1-mediated translation remain unclear. PAR-CLIP of LARP1 revealed its direct and dynamic interactions with RP mRNAs through pyrimidine-enriched sequences in the 5M-bM-^@M-^YUTR of RP mRNAs when mTOR activity is inhibited. Importantly, this LARP1 is a direct substrate of mTORC1 and S6K1/Akt, and phosphorylated LARP1 scaffolds mTORC1 on translation-competent mRNAs to facilitate 4EBP1 and S6K1 phosphorylation. Ablation of LARP1 causes multiple defects in the processes of translation including abnormal eIF4G1 interaction with RP mRNAs and inefficient RP mRNA elongation thereby reducing ribosome biogenesis and cell proliferation. These observations illustrate that LARP1 functions both an effector and a regulator for local mTORC1 activity, and acts as a molecular switch for ribosome biogenesis by sensing growth factor/nutrient signaling. LARP1-bound RNA regions were sequenced from HEK293T cells under growing or mTOR-inactive conditions. In parallel, mRNA abundance was quantified, in biological duplicate, from HEK293T cells under the same conditions.

2014-07-31 | E-GEOD-59599 | biostudies-arrayexpress

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