Rbm3 deficiency leads to transcriptome-wide splicing alterations DOI Creative Commons
Steffen Erkelenz, Marta Grzonka, Antonios Papadakis

et al.

RNA Biology, Journal Year: 2024, Volume and Issue: 21(1), P. 1 - 13

Published: Oct. 10, 2024

(RNA-binding motif protein 3) is a stress responsive gene, which maintains cellular homeostasis and promotes survival upon various harmful stimuli. Rbm3 shows conserved structural molecular similarities to heterogeneous nuclear ribonucleoproteins (hnRNPs), regulate all steps of the mRNA metabolism. Growing evidence pointing towards broader role in gene expression. Here, we demonstrate that deficiency linked transcriptome-wide pre-mRNA splicing alterations, can be reversed through co-expression from cDNA. Using an MS2 tethering assay, show regulates splice site selection similar other hnRNP proteins when recruited between two competing 5

Language: Английский

ASO targeting RBM3 temperature‐controlled poison exon splicing prevents neurodegeneration in vivo DOI
Marco Preußner, Heather Smith, Daniel T. Hughes

et al.

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(5)

Published: March 22, 2023

Language: Английский

Citations

25
HNRNPH1 regulates the neuroprotective cold‐shock protein RBM3 expression through poison exon exclusion DOI Creative Commons
Julie Qiaojin Lin, Deepak Khuperkar,

Sofia Pavlou

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(14)

Published: May 30, 2023

Abstract Enhanced expression of the cold‐shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and vivo . Whilst upstream signalling pathways leading to RBM3 have been described, precise molecular mechanism cold induction remains elusive. To identify temperature‐dependent modulators RBM3, we performed a genome‐wide CRISPR‐Cas9 knockout screen using RBM3‐reporter human iPSC‐derived neurons. We found that mRNA levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being strongest positive regulator. Splicing analysis revealed moderate hypothermia significantly represses inclusion poison exon, which, when retained, targets for nonsense‐mediated decay. Importantly, show HNRNPH1 mediates this cold‐dependent exon skipping via its thermosensitive interaction G‐rich within exon. Our study provides novel mechanistic insights into regulation further therapeutic strategies.

Language: Английский

Citations

16
An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division DOI Creative Commons
Caroline Dalgliesh,

Saad Aldalaqan,

Christian Atallah

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(3), P. 877 - 902

Published: Jan. 2, 2025

The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation inclusion non-coding 'poison exons' (PEs) target transcripts nonsense-mediated decay. importance SR PE during animal development is largely unknown despite ultra-conservation across genomes. To address this, we used mouse genetics to disrupt an ultra-conserved in the Tra2b gene encoding Tra2β. Focussing on germ cell development, found deletion causes azoospermia due catastrophic death meiotic prophase. Failure proceed through meiosis was associated with increased expression sufficient drive aberrant Tra2β hyper-responsive splice patterns. Although prophase, spared earlier mitotically active cells, even though these still required function. Our data indicate control prevents accumulation toxic levels incompatible This unexpected connection male fertility helps explain indicates evaluating function models.

Language: Английский

Citations

0
Poison exons: tuning RNA splicing for targeted gene regulation DOI Creative Commons

Christopher R. Neil,

Cassandra Schaening-Burgos,

Maria S. Alexis

et al.

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
PTK6 drives HNRNPH1 phase separation to activate autophagy and suppress apoptosis in colorectal cancer DOI

Bingyuan Chen,

Bowen Liu,

Junnan Chen

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Macroautophagy/autophagy is the principal mechanism that mediates delivery of various cellular cargoes to lysosomes for degradation and recycling, has been reported play a crucial role in colorectal cancer (CRC) pathogenesis progression. Targeting autophagy may be promising therapeutic strategy CRC. However, specific functions potential mechanisms CRC remain unclear. In present study, we discovered PTK6 (protein tyrosine kinase 6) could activate inhibit apoptosis. physically interacted with HNRNPH1 mediated phosphorylation at Y210 HNRNPH1, which promoted latter's liquid-liquid phase separation (LLPS). Furthermore, LLPS formed biomolecular condensates triggered splicing-switching NBR1 exon 10 inclusion transcript, thereby activating suppressing apoptosis Additionally, PDO CDX models indicated tilfrinib, an inhibitor targeting PTK6, growth. Overall, our findings reveal novel PTK6-HNRNPH1-NBR1 regulatory axis provide therapy target

Language: Английский

Citations

0
Promoting health and survival through lowered body temperature DOI
Bruno Conti,

Rafael de Cabo

Nature Aging, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Language: Английский

Citations

0
Cold-shock proteome of myoblasts reveals role of RBM3 in promotion of mitochondrial metabolism and myoblast differentiation DOI Creative Commons

Paulami Dey,

Srujanika Rajalaxmi, Pushpita Saha

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: April 30, 2024

Adaptation to hypothermia is important for skeletal muscle cells under physiological stress and used therapeutic (mild at 32 °C). We show that hypothermic preconditioning °C 72 hours improves the differentiation of myoblasts using both C2C12 primary isolated from 3 month 18-month-old mice. analyzed cold-shock proteome exposed (32 6 48 h) identified significant changes in pathways related RNA processing central carbon, fatty acid, redox metabolism. The analysis revealed levels protein RBM3, an RNA-binding protein, increases with acute chronic exposure stress, necessary enhanced maintenance mitochondrial also overexpression RBM3 37 sufficient promote metabolism, cellular proliferation, myoblasts. Proteomic overexpressing enrichment involved acid metabolism electron transport chain. Overall, we a critical factor can be controlling metabolic network

Language: Английский

Citations

3
Manipulating and studying gene function in human pluripotent stem cell models DOI Creative Commons
Elisa Balmas,

Federica Sozza,

Sveva Bottini

et al.

FEBS Letters, Journal Year: 2023, Volume and Issue: 597(18), P. 2250 - 2287

Published: July 31, 2023

Human pluripotent stem cells (hPSCs) are uniquely suited to study human development and disease promise revolutionize regenerative medicine. These applications rely on robust methods manipulate gene function in hPSC models. This comprehensive review aims both empower scientists approaching the field update experienced cell biologists. We begin by highlighting challenges with manipulating expression hPSCs their differentiated derivatives, relevant solutions (transfection, transduction, transposition, genomic safe harbor editing). then outline how perform constitutive or inducible loss-, gain-, change-of-function experiments models, using historical (RNA interference, transgenesis, homologous recombination) modern programmable nucleases (particularly CRISPR/Cas9 its i.e., CRISPR activation, base editing, prime further describe extension of these approaches for arrayed pooled functional studies, including emerging single-cell methods, related design analytical bioinformatic tools. Finally, we suggest some directions future advancements all areas. Mastering combination transformative technologies will unprecedented advances biology

Language: Английский

Citations

8
Mild hypothermia promotes neuronal differentiation of human neural stem cells via RBM3-SOX11 signaling pathway DOI Creative Commons

Yuxiao Ma,

Zhenghui He,

Jiangchang Wang

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(4), P. 109435 - 109435

Published: March 6, 2024

Both therapeutic hypothermia and neural stem cells (NSCs) transplantation have shown promise in neuroprotection repair after brain injury. However, the effects of on neuronal differentiation NSCs are not elucidated. In this study, we aimed to investigate whether mild promoted cultured transplanted human (hNSCs). A significant increase rate hNSCs was found when exposed 35°C, from 33% 45%

Language: Английский

Citations

2
Trends and hotspots of the neuroprotection of hypothermia treatment: A bibliometric and visualized analysis of research from 1992 to 2023 DOI Creative Commons
Yang Zhang,

Miaowen Jiang,

Song Baoying

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(6)

Published: June 1, 2024

Abstract Aim Recent studies have extensively investigated hypothermia as a therapeutic approach for mitigating neural damage. Despite this, bibliometric analyses specifically focusing on this area remain scarce. Consequently, study aims to comprehensively outline the historical framework of research and pinpoint future directions trends. Methods Articles spanning from 2003 2023, relevant both “neuroprotection” “hypothermia”, were sourced Web Science Core Collection. The CiteSpace software facilitated comprehensive evaluation analysis these publications. This included examining annual productivity, collaboration among nations, institutions, authors, well network co‐cited references, authors journals, co‐occurrence keywords, their respective clusters trends, all which visualized. Results 2103 articles neuroprotection effects hypothermia, noting consistent increase in publications since 1992. United States, University California System, Ji Xunming emerged most productive nation, institution, author, respectively. Analysis top 10 revealed that seven focused infants with hypoxic–ischemic encephalopathy, while three addressed cardiac arrest. Shankaran S journal Stroke frequently author journal, Keyword cluster identified ischemic stroke primary focus therapy historically, arrest neonatal encephalopathy emerging current foci. Conclusions neuroprotective suggest may mitigate damage associated conditions. However, application treatment remains confined animal models vitro studies, notable absence evidence multicenter randomized controlled trials (RCTs). Further is required address gap.

Language: Английский

Citations

2