Pre-mRNA splicing and its cotranscriptional connections

Trends in Genetics, Год журнала: 2023, Номер 39(9), С. 672 - 685

Опубликована: Май 24, 2023

Язык: Английский

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M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1

Cancer Letters, Год журнала: 2024, Номер 598, С. 217085 - 217085

Опубликована: Июль 2, 2024

LncRNA plays a crucial role in cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved colorectal (CRC) progression. We identified FAM83H-AS1 as tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues adjacent normal tissues. In vitro vivo experiments revealed that knockdown cells inhibited tumor proliferation metastasis, vice versa. M6A modification is for RNA stability through writer METTL3 readers IGF2BP2/IGFBP3. PTBP1-an binding protein-is responsible function CRC. T4 (1770-2440 nt) T5 (2440-2743 on exon 4 provide platform PTBP1 RRM2 interactions. Our results demonstrated m6A dysregulated oncogenic by phosphorylated its splicing effect. patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed growth gastrointestinal (GI) tumors, not only also GC ESCC. The combination oxaliplatin/cisplatin compared with treatment either agent alone. Notably, there was pathological complete response all these three GI cancers. findings suggest targeted therapy would benefit patients primarily receiving platinum-based

Язык: Английский

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Alternative splicing coupled to nonsense-mediated decay coordinates downregulation of non-neuronal genes in developing mouse neurons

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Июнь 20, 2024

Abstract Background The functional coupling between alternative pre-mRNA splicing (AS) and the mRNA quality control mechanism called nonsense-mediated decay (NMD) can modulate transcript abundance. Previous studies have identified several examples of such a regulation in developing neurons. However, systems-level effects AS-NMD this context are poorly understood. Results We developed an R package, factR2, which offers comprehensive suite analysis functions. Using tool, we conducted longitudinal gene expression pluripotent stem cells undergoing induced neuronal differentiation. Our uncovers hundreds events with significant potential to regulate expression. Notably, is significantly overrepresented specific groups developmentally downregulated genes. Particularly strong association downregulation detected for cassette exons stimulating NMD upon their inclusion into mature mRNA. By combining bioinformatic analyses CRISPR/Cas9 genome editing other experimental approaches show that NMD-stimulating regulated by RNA-binding protein PTBP1 dampen genes also provided evidence mRNAs temporally coordinated NMD-independent repression mechanisms. Conclusions study provides accessible workflow discovery prioritization targets. It further argues pathway plays widespread role neurons facilitating functionally related non-neuronal

Язык: Английский

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Regulation of alternative splicing: Functional interplay with epigenetic modifications and its implication to cancer

Wiley Interdisciplinary Reviews - RNA, Год журнала: 2023, Номер 15(1)

Опубликована: Сен. 12, 2023

Abstract Eukaryotic gene expression is intricately regulated at multiple levels. The protein‐coding genes are first transcribed as pre‐mRNAs in the nucleus and undergo a series of RNA processing steps before being transported into cytoplasm for translation. During processing, most human (>95%) alternative splicing to generate mRNA isoforms from single gene, which effectively diversifies genome complexity. Since occurs co‐transcriptionally, regulation layers often show functional interactions with each other. In this review, we provide brief overview three different (controlled by machinery, transcription process, chromatin structure), emphasizing regulatory roles epigenetic modifications crosstalk between these layers. Specifically, categorize major effects on types: affecting rate, factor recruitment, or expression/activity factor. dysregulation epigenetics extremely common cancer, also discuss potential mechanisms how changes can lead their consequences. We aim insights complicated layers, will shed light novel approaches modulate disease‐related dysregulation. This article categorized under: Processing > 3′ End Splicing Mechanisms Regulation/Alternative Disease Development

Язык: Английский

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Characterization of dsRNA binding proteins through solubility analysis identifies ZNF385A as a dsRNA homeostasis regulator

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 11, 2025

Double-stranded RNA (dsRNA) binding proteins (dsRBPs) play crucial roles in various cellular processes, especially the innate immune response. Comprehensive characterization of dsRBPs is essential to understand intricate mechanisms for dsRNA sensing and Traditional methods have predominantly relied on affinity purification, favoring isolation strong binders. Here, we adopt proteome integral solubility alteration (PISA) workflow characterizing dsRBPs, resulting observation 18 known identification 200 potential dsRBPs. Next, focus zinc finger protein 385 A (ZNF385A) discover that its knockout activates transcription interferon-β absence immunogenic stimuli. The ZNF385A elevates level endogenous dsRNAs, transcripts associated with retroelements, such as short interspersed nuclear element (SINE), long (LINE), terminal repeat (LTR). Moreover, loss enhances bioactivity 5-Aza-2'-deoxycytidine (5-AZA-CdR) tumor-killing effect NK cells. Our findings greatly expand dsRBP reservoir contribute understanding homeostasis.

Язык: Английский

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Epigenetic Regulation and Therapeutic Targeting of Alternative Splicing Dysregulation in Cancer

Pharmaceuticals, Год журнала: 2025, Номер 18(5), С. 713 - 713

Опубликована: Май 12, 2025

Alternative splicing enables a single precursor mRNA to generate multiple isoforms, leading protein variants with different structures and functions. Abnormal alternative is frequently associated cancer development progression. Recent studies have revealed complex dynamic interplay between epigenetic modifications splicing. On the one hand, dysregulated changes can alter patterns; on other events influence landscapes. The reversibility of makes drugs, both approved investigational, attractive therapeutic options. This review provides comprehensive overview bidirectional relationship regulation in cancer. It also highlights emerging approaches aimed at correcting abnormalities, special focus drug-based strategies. These include inhibitors, antisense oligonucleotides (ASOs), small-molecule compounds, CRISPR-Cas9 genome editing, SMaRT (splice-switching molecule) technology. By integrating recent advances research strategies, this novel insights into molecular mechanisms supports more precise effective therapies targeting aberrant

Язык: Английский

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Regulation of alternative splicing and polyadenylation in neurons

Life Science Alliance, Год журнала: 2023, Номер 6(12), С. e202302000 - e202302000

Опубликована: Окт. 4, 2023

Cell-type–specific gene expression is a fundamental feature of multicellular organisms and achieved by combinations regulatory strategies. Although cell-restricted transcription perhaps the most widely studied mechanism, co-transcriptional post-transcriptional processes are also central to spatiotemporal control functions. One general category involves generation multiple transcript isoforms from an individual gene, whose balance cell specificity frequently tightly regulated via diverse The nervous system makes particularly extensive use cell-specific isoforms, specializing neural function genes that expressed more broadly. Here, we review strategies RNA-binding proteins direct neural-specific isoform processing. These include various classes alternative splicing polyadenylation events, both which broadly diversify transcriptome. Importantly, global alterations characteristic many pathologies, recent genetic studies demonstrate how misregulation can directly cause mutant phenotypes.

Язык: Английский

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LINE1 modulate human T cell function by regulating protein synthesis during the life span

Science Advances, Год журнала: 2024, Номер 10(41)

Опубликована: Окт. 9, 2024

The molecular mechanisms responsible for the heightened reactivity of quiescent T cells in human early life remain largely elusive. Our previous research identified that adult naïve CD4

Язык: Английский

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A Simplified and Effective Approach for the Isolation of Small Pluripotent Stem Cells Derived from Human Peripheral Blood

Biomedicines, Год журнала: 2023, Номер 11(3), С. 787 - 787

Опубликована: Март 5, 2023

Pluripotent stem cells are key players in regenerative medicine. Embryonic pluripotent cells, despite their significant advantages, associated with limitations such as inadequate availability and the ethical dilemmas isolation clinical use. The discovery of very small embryonic-like (VSEL) addressed aforementioned limitations, but technique remains a challenge due to cell size efficiency isolation. Here, we report simplified effective approach for derived from human peripheral blood. Our results high yield blood (SBSC) population, which expresses embryonic markers (e.g., Nanog, SSEA-3) Yamanaka factors. Further, fraction SBSCs also co-express hematopoietic CD45 CD90) and/or mesenchymal CD29, CD105 PTH1R), suggesting mixed population. Finally, quantitative proteomic profiling reveals that contain various (CD9, ITGA6, MAPK1, MTHFD1, STAT3, HSPB1, HSPA4), Transcription reg complex factors STAT5B, PDLIM1, ANXA2, ATF6, CAMK1). In conclusion, present novel, isolating process yields an abundant population small-sized characteristics pluripotency

Язык: Английский

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PTBP1 enforces ATR-CHK1 signaling determining the potency of CDC7 inhibitors

iScience, Год журнала: 2023, Номер 26(6), С. 106951 - 106951

Опубликована: Май 26, 2023

CDC7 kinase is crucial for DNA replication initiation and fork processing. inhibition mildly activates the ATR pathway, which further limits origin firing; however, to date relationship between remains controversial. We show that inhibitors are either synergistic or antagonistic depending on degree of each individual kinase. find Polypyrimidine Tract Binding Protein 1 (PTBP1) important activity in response genotoxic agents. Compromised PTBP1 expression makes cells defective RPA recruitment, genomically unstable, resistant inhibitors. deficiency affects splicing many genes indicating a multifactorial impact drug response. an exon skipping event RAD51AP1 contributes checkpoint PTBP1-deficient cells. These results identify as key factor stress define how modulates

Язык: Английский

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