RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer

Nature, Год журнала: 2023, Номер 617(7959), С. 147 - 153

Опубликована: Март 22, 2023

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation correlated with the dissemination of metastases 1–3 . Here we analysed RNA splicing data a large cohort primary tumours identify differentially spliced events that correlate progression. De novo motif analysis these detected enrichment motifs similarity RBFOX2 motif. Overexpression in patient-derived xenograft (PDX) cell line drastically reduced potential cells vitro vivo, whereas depletion pancreatic tumour lines increased cells. These findings support role as potent suppressor PDA. RNA-sequencing target genes revealed RHO GTPase pathways, suggesting activity cytoskeletal organization focal adhesion formation. Modulation RBFOX2-regulated events, such via myosin phosphatase RHO-interacting protein (MPRIP), associated metastases, altered induction Our results implicate splicing-regulatory function suggest therapeutic approach for

Язык: Английский

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A H3K27M-targeted vaccine in adults with diffuse midline glioma

Nature Medicine, Год журнала: 2023, Номер 29(10), С. 2586 - 2592

Опубликована: Сен. 21, 2023

Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses control H3K27M+ tumors major histocompatibility complex-humanized mice. Here we describe first-in-human treatment with H3K27M-vac eight adult patients progressive midline glioma on compassionate use basis. Five received combined anti-PD-1 based physician's discretion. Repeat vaccinations were safe and induced CD4+ T cell-dominated, five across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months median overall 12.8 months. One patient strong cell response showed pseudoprogression followed by sustained complete remission for >31 Our data demonstrate safety immunogenicity

Язык: Английский

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Massively parallel identification of mRNA localization elements in primary cortical neurons

Nature Neuroscience, Год журнала: 2023, Номер unknown

Опубликована: Янв. 16, 2023

Abstract Cells adopt highly polarized shapes and form distinct subcellular compartments in many cases due to the localization of mRNAs specific areas, where they are translated into proteins with local functions. This mRNA is mediated by cis -regulatory elements mRNAs, commonly called ‘zipcodes’. Although there hundreds localized only a few zipcodes have been characterized. Here we describe novel neuronal zipcode identification protocol (N-zip) that can identify across 3′ untranslated regions. approach combines method separating principal neurons—cell bodies neurites—with massively parallel reporter assay. N-zip identifies let-7 binding site (AU) n motif as de novo mouse primary cortical neurons. Our analysis also provides, our knowledge, first demonstration an miRNA affecting suggests strategy for detecting more zipcodes.

Язык: Английский

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The metazoan landscape of mitochondrial DNA gene order and content is shaped by selection and affects mitochondrial transcription

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Янв. 23, 2023

Mitochondrial DNA (mtDNA) harbors essential genes in most metazoans, yet the regulatory impact of multiple evolutionary mtDNA rearrangements has been overlooked. Here, by analyzing mtDNAs from ~8000 metazoans we found high gene content conservation (especially protein and rRNA genes), codon preferences for mtDNA-encoded tRNAs across metazoans. In contrast, order (MGO) was selectively constrained within but not between phyla, certain stretches (ATP8-ATP6, ND4-ND4L) were highly conserved Since with different MGOs diverge transcription, hypothesized that affected transcriptional patterns. As a first step to test this hypothesis, analyzed available RNA-seq data 53 polycistron transcripts constitute small fraction steady-state RNA, enriched polycistronic boundaries calculating read densities junctions couples encoded either same strand (SSJ) or strands (DSJ). We organisms whose is organized alternating reverse-strand/forward-strand blocks (mostly arthropods), displayed significantly reduced DSJ counts, contrast are preferentially one (all chordates). Our findings suggest likely regulation.

Язык: Английский

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GENA-LM: A Family of Open-Source Foundational DNA Language Models for Long Sequences

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июнь 13, 2023

Recent advancements in genomics, propelled by artificial intelligence, have unlocked unprecedented capabilities interpreting genomic sequences, mitigating the need for exhaustive experimental analysis of complex, intertwined molecular processes inherent DNA function. A significant challenge, however, resides accurately decoding which inherently involves comprehending rich contextual information dispersed across thousands nucleotides. To address this need, we introduce GENA-LM, a suite transformer-based foundational language models capable handling input lengths up to 36,000 base pairs. Notably, integration newly-developed Recurrent Memory mechanism allows these process even larger segments. We provide pre-trained versions demonstrating their capability fine-tuning and addressing spectrum complex biological tasks with modest computational demands. While already achieved breakthroughs protein biology, GENA-LM showcases similarly promising potential reshaping landscape genomics multi-omics data analysis. All are publicly available on GitHub https://github.com/AIRI-Institute/GENA LM HuggingFace https://huggingface.co/AIRI-Institute.

Язык: Английский

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Single-cell transcriptomics of the human parasite Schistosoma mansoni first intra-molluscan stage reveals tentative tegumental and stem-cell regulators

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Март 12, 2024

Abstract Schistosomiasis is a major Neglected Tropical Disease, caused by the infection with blood flukes in genus Schistosoma . To complete life cycle, parasite undergoes asexual and sexual reproduction within an intermediate snail host definitive mammalian host, respectively. The intra-molluscan phase provides critical amplification step that ensures successful transmission. However, cellular molecular mechanisms underlying development of stages remain poorly understood. Here, single cell suspensions from S. mansoni mother sporocysts were produced sequenced using droplet-based 10X Genomics Chromium platform. Six clusters comprising two tegument, muscle, neuron, parenchyma stem/germinal identified validated situ hybridisation. Gene Ontology term analysis predicted key biological processes for each clusters, including three sub-clusters. Furthermore, putative transcription factors tegument may play roles during interaction host.

Язык: Английский

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AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization

Nature, Год журнала: 2024, Номер 628(8007), С. 400 - 407

Опубликована: Март 13, 2024

Язык: Английский

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Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Фев. 26, 2024

Abstract Background Hypoxia in solid tumors is an important source of chemoresistance that can determine poor patient prognosis. Such relies on the presence cancer stem cells (CSCs), and hypoxia promotes their generation through transcriptional activation by HIF transcription factors. Methods We used ovarian (OC) cell lines, xenograft models, OC samples, databases, induced pluripotent (iPSCs) Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). Results Here, we show induces CSC formation PLD2 gene. Mechanistically, HIF-1α activates response elements, both overexpression lead to increased accessibility around stemness genes, detected ATAC-seq, at sites bound AP-1 This turn provokes a rewiring including SOX2 , SOX9 or NOTCH1 . also leads decreased survival, enhanced tumor growth formation, iPSCs reprograming, confirming its role dedifferentiation stem-like phenotype. Importantly, hypoxia-induced dependent expression, demonstrating major determinant de-differentiation hypoxic conditions. Finally, demonstrate high expression increases cisplatin carboplatin treatments, vitro vivo, while pharmacological inhibition restores sensitivity. Conclusions Altogether, our work highlights importance HIF-1α-PLD2 axis proposes alternative treatment patients with expression.

Язык: Английский

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GENA-LM: a family of open-source foundational DNA language models for long sequences

Nucleic Acids Research, Год журнала: 2025, Номер 53(2)

Опубликована: Янв. 11, 2025

Abstract Recent advancements in genomics, propelled by artificial intelligence, have unlocked unprecedented capabilities interpreting genomic sequences, mitigating the need for exhaustive experimental analysis of complex, intertwined molecular processes inherent DNA function. A significant challenge, however, resides accurately decoding which inherently involves comprehending rich contextual information dispersed across thousands nucleotides. To address this need, we introduce GENA language model (GENA-LM), a suite transformer-based foundational models capable handling input lengths up to 36 000 base pairs. Notably, integrating newly developed recurrent memory mechanism allows these process even larger segments. We provide pre-trained versions GENA-LM, including multispecies and taxon-specific models, demonstrating their capability fine-tuning addressing spectrum complex biological tasks with modest computational demands. While already achieved breakthroughs protein biology, GENA-LM showcases similarly promising potential reshaping landscape genomics multi-omics data analysis. All are publicly available on GitHub (https://github.com/AIRI-Institute/GENA_LM) HuggingFace (https://huggingface.co/AIRI-Institute). In addition, web service (https://dnalm.airi.net/) allowing user-friendly annotation models.

Язык: Английский

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Deep learning and ensemble deep learning for circRNA-RBP interaction prediction in the last decade: A review

Engineering Applications of Artificial Intelligence, Год журнала: 2023, Номер 123, С. 106352 - 106352

Опубликована: Май 2, 2023

Язык: Английский

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