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An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

ABSTRACT: An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

PROVIDER: PRJNA641118 | ENA |

REPOSITORIES: ENA

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An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

Project description:We recently described aberrant cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as a new hallmark of amyotrophic lateral sclerosis (ALS). However the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep-sequencing of nuclear and cytoplasmic fractions of hiPSCs undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic (but not nuclear) abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins (RBPs). Remarkably, TDP-43, SFPQ and FUS - RBPs known for nuclear-to-cytoplasmic mislocalization in ALS - avidly and specifically bind to this aberrant cytoplasmic pool of IRTs, as opposed to any individual IRT. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets.

2020-12-31 | GSE152983 | GEO

Aberrant cytoplasmic intron retention is a blueprint for RNA binding protein mislocalization in VCP-related amyotrophic lateral sclerosis.

Project description: Not available

| S-EPMC8370440 | biostudies-literature

BLUEPRINT hematopoietic progenitors

Project description:BLUEPRINT hematopoietic progenitors

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Synthetic 5’ UTRs can either up- or down-regulate expression upon RBP binding

Project description:The construction of complex gene regulatory networks requires both inhibitory and up-regulatory modules. However, the vast majority of RNA-based regulatory “parts” are inhibitory. Using a synthetic biology approach combined with SHAPE-Seq, we explored the regulatory effect of RBP-RNA interactions in bacterial 5’-UTRs. By positioning a library of RNA hairpins upstream of a reporter gene and co-expressing them with the matching RBP, we observed a set of regulatory responses, including translational stimulation, translational repression, and cooperative behavior. Our combined approach revealed three distinct states in-vivo: in the absence of RBPs, the RNA molecules can be found either in a molten state that is amenable to translation, or a structured phase that inhibits translation. In the presence of RBPs, the RNA molecules are in a semi-structured phase with partial translational capacity. Our work provides new insight into RBP-based regulation and a blueprint for designing complete gene regulatory circuits at the post-transcriptional level.

2019-04-03 | GSE129163 | GEO

Histone H3/H4 chaperone CHAF1B prevents the mislocalization of CENP-A for chromosomal stability

Project description:Mislocalization of CENP-A to non-centromeric regions contributes to chromosomal instability (CIN). Here, we defined a role for the histone H3/H4 chaperone CHAF1B in preventing mislocalization of CENP-A and CIN.

2023-05-05 | GSE227373 | GEO

DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of H3-H4 supply chains

Project description:The centromeric histone H3 variant CENP-A is overexpressed in many cancers. Mislocalization of CENP-A to non-centromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. Despite these observations, pathways that promote and prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen to identify regulators of CENP-A localization. We identified DNAJC9, a J-domain protein as a lead candidate from the screen and showed that cells depleted for DNAJC9 exhibit mislocalization of CENP-A, enrichment of CENP-A in chromatin, and CIN phenotypes. Global interactome analysis showed an enhanced interaction of CENP-A with the replication-associated H3-H4 chaperone MCM2 in DNAJC9-depleted cells and co-depletion of MCM2 and DNAJC9 suppressed CENP-A mislocalization. Furthermore, we showed that cells ablated for the ability of DNAJC9 to promote the proper folding of H3–H4, exhibit CENP-A mislocalization. CUT&RUN Sequencing analysis of genome-wide CENP-A occupancy in DNAJC9-depleted cells identified 16,603 sites of non-centromeric localization, that broadly overlapped with open chromatin regions. Our comprehensive analysis has identified factors that prevent mislocalization of CENP-A and has defined DNAJC9 as an important safeguard that prevents CENP-A mislocalization and CIN.

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Genome-wide transcriptional regulation by RBP-J

Project description:We sequenced mRNAs from bone borrow derived macrophages derived from the control (WT) and RBP-J conditional knockout mice (RBP-J KO; Rbpj f/f;LysM cre).

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Genome-wide microRNA expression in WT and RBP-J KO BMDMs

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2019-12-11 | GSE103220 | GEO

Transcriptome changes caused by RBP-L knockdown in rice grains

Project description:A T-DNA insertion within RBP-L 3’UTR resulted in 10-25% expression level of RBP-L gene compared to wild-type. The reduced expression of RBP-L caused partial mis-localization of glutelin and prolamine RNAs and conferred other general growth defects including dwarfism, late flowering and smaller seeds. Transcriptome analysis showed that RBP-L knockdown greatly affected the expression of prolamine family genes and many genes invovled in essential biological pathways during plant development.

2019-05-22 | GSE124301 | GEO

Dbf4-Dependent Kinase (DDK)-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A in Saccharomyces cerevisiae

Project description:Restricting the localization of the centromeric histone H3 variant CENP-A to centromeres is essential to prevent chromosomal instability (CIN). Mislocalization of overexpressed CENP-A contributes to CIN in yeast, fly, and human cells. CENP-A is overexpressed in many cancers. Therefore, defining mechanisms that prevent CENP-A mislocalization will help us understand how CENP-A overexpression contributes to CIN in cancer. A genome-wide screen to characterize essential genes required for growth when CENP-A is overexpressed identified the replication initiation Dbf4-Dependent Kinase (DDK) complex. We show that DDK regulates ubiquitin-mediated proteolysis of Cse4 and prevents mislocalization of Cse4 independently of its role in DNA replication.

2020-04-04 | GSE148068 | GEO

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