The RNA Revolution in the Central Molecular Biology Dogma Evolution DOI Open Access
William A. Haseltine, Roberto Patarca

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(23), С. 12695 - 12695

Опубликована: Ноя. 26, 2024

Human genome projects in the 1990s identified about 20,000 protein-coding sequences. We are now RNA revolution, propelled by realization that genes determine phenotype beyond foundational central molecular biology dogma, stating inherited linear pieces of DNA transcribed to RNAs and translated into proteins. Crucially, over 95% genome, initially considered junk between genes, encodes essential, functionally diverse non-protein-coding RNAs, raising gene count at least one order magnitude. Most phenotype-determining changes regulatory areas control can directly or indirectly phenotypes regulating protein function, transferring information within organisms, generating DNA. also exhibit high structural, functional, biomolecular interaction plasticity modified via editing, methylation, glycosylation, other mechanisms, which bestow them with intra- extracellular functions without altering underlying is, therefore, currently primary determinant cellular populational functional diversity, disease-linked structural variations, cell function regulation. As demonstrated RNA-based coronavirus vaccines' success, technology is transforming medicine, agriculture, industry, as did advent recombinant 1980s.

Язык: Английский

Connecting genotype and phenotype in minor spliceosome diseases DOI Open Access
Antto J. Norppa, Mariia Shcherbii, Mikko J. Frilander

и другие.

RNA, Год журнала: 2025, Номер 31(3), С. 284 - 299

Опубликована: Янв. 6, 2025

Minor spliceosome is responsible for recognizing and excising a specific subset of divergent introns during the pre-mRNA splicing process. Mutations in unique snRNA protein components minor are increasingly being associated with variety germline somatic human disorders, collectively termed as spliceosomopathies. Understanding mechanistic basis these diseases has been challenging due to limited functional information on many components. However, recently published cryo-electron microscopy (cryo-EM) structures various assembly intermediates have marked significant advancement elucidating roles splicing. These structural breakthroughs not only enhanced our comprehension spliceosome's functionality but also shed light how disease-associated mutations disrupt its functions. Consequently, research focus now shifting toward investigating defects translate into broader pathological processes within gene expression pathways. Here we outline current knowledge spliceosome, explore consequences mutations, discuss emerging challenges connecting molecular dysfunctions clinical phenotypes.

Язык: Английский

Процитировано

0
Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing DOI
Jack Humphrey,

Erica Brophy,

Roman Kosoy

и другие.

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Язык: Английский

Процитировано

0
Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis DOI Creative Commons
Jun Inamo,

Joshua Keegan,

Alec Griffith

и другие.

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(6)

Опубликована: Март 16, 2025

Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset crucial establishing Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) characterize the immunophenotypes blood from individuals (ARIs) identified through presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared patients established RA people healthy control group. We significant cell expansions ARIs controls, including CCR2+CD4+ T cells, peripheral helper (Tph) type 1 CXCR5+CD8+ cells. also found that CD15+ classical monocytes were specifically expanded ACPA-negative FDRs, an activated PAX5lo naive B population was ACPA-positive FDRs. Further, uncovered molecular phenotype expressing high levels Th17- Th22-related signature transcripts CCR6, IL23R, KLRB1, CD96, IL22. Our integrated study provides promising approach identify targets improve strategy development for RA.

Язык: Английский

Процитировано

0
The epigenetic landscape of fate decisions in T cells DOI
Atishay Jay, Carlos M. Pondevida, Golnaz Vahedi

и другие.

Nature Immunology, Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

Язык: Английский

Процитировано

0
Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases DOI Creative Commons
Chi Tian, Yuntian Zhang,

Yihan Tong

и другие.

Nature Genetics, Год журнала: 2024, Номер 56(12), С. 2739 - 2752

Опубликована: Дек. 1, 2024

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative ~1 M peripheral blood mononuclear cells from 474 healthy donors the Asian Immune Diversity Atlas. We identify widespread differential splicing, most of which cell-type-specific. 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes 107 dynamic sQTLs. Colocalization between cis-eQTLs trans-sQTLs revealed a cell-type-specific regulatory relationship HNRNPLL PTPRC. observed an enrichment cis-sQTL effects autoimmune inflammatory disease heritability. Specifically, functionally validated Asian-specific sQTL disrupting 5′ splice site TCHP exon 4 that putatively modulates risk Graves' East populations. Our work highlights impact ancestral diversity on provides roadmap dissect its role diseases at single-cell resolution. This analysis RNA sequencing data for individuals Atlas links variation with risk.

Язык: Английский

Процитировано

3
Multi-omic profiling of pathogen-stimulated primary immune cells DOI Creative Commons
Renee Salz, Emil E. Vorsteveld, Caspar I. van der Made

и другие.

iScience, Год журнала: 2024, Номер 27(8), С. 110471 - 110471

Опубликована: Июль 6, 2024

Язык: Английский

Процитировано

0
Functional and dynamic profiling of transcript isoforms reveals essential roles of alternative splicing in interferon response DOI Creative Commons
Mahoko Takahashi Ueda, Jun Inamo, Fuyuki Miya

и другие.

Cell Genomics, Год журнала: 2024, Номер 4(10), С. 100654 - 100654

Опубликована: Сен. 16, 2024

Type I interferon (IFN-I) plays an important role in the innate immune response through inducing IFN-I-stimulated genes (ISGs). However, how alternative splicing (AS) events, especially over time, affect their function remains poorly understood. We generated annotation (113,843 transcripts) for human B cells called isoISG using high-accuracy long-read sequencing data from PacBio Sequel II/IIe. Transcript isoform profiling revealed that switching occurred early to IFN-I so ISGs would gain functional domains (e.g., C4B) or higher protein production IRF3). Conversely, isoforms lacking increased during late phase of response, mainly due intron retention events. This suggests both triggers and terminates responses at translation levels. Furthermore, genetic variants influencing ratio were associated with immunological infectious diseases. AS has essential roles regulating

Язык: Английский

Процитировано

0
Long-Read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons DOI Creative Commons
Jishu Xu, Michaela Hörner, Elena Buena‐Atienza

и другие.

Опубликована: Ноя. 11, 2024

Abstract Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution transcript diversity, alternative splicing, and transcript-specific regulation. In this study, we employed nanopore long-read to profile the transcriptomes human fibroblasts, induced pluripotent stem cells, cell-derived cortical neurons, identifying extensive diversity with 15,072 transcripts in 13,048 12,759 cells. Our analyses uncovered 35,519 differential expression events 5,135 usage events, underscoring complexity transcriptomic regulation across these cell types. Importantly, integrating analyses, gained deeper insights into dynamics that are not captured gene-level alone. Notably, highlighted changes disease-relevant genes such as APP, KIF2A , BSCL2 associated Alzheimer’s disease, neuronal migration disorders, degenerative axonopathies, respectively. This added emphasizes significance transcript- level variations often remain hidden traditional gene analyses. Overall, our work provides a framework for understanding both specialized types, which can be used investigate disease states. Additionally, study underscores utility advancing neurodevelopmental neurodegenerative diseases, paving way therapeutic targets.

Язык: Английский

Процитировано

0
The RNA Revolution in the Central Molecular Biology Dogma Evolution DOI Open Access
William A. Haseltine, Roberto Patarca

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(23), С. 12695 - 12695

Опубликована: Ноя. 26, 2024

Human genome projects in the 1990s identified about 20,000 protein-coding sequences. We are now RNA revolution, propelled by realization that genes determine phenotype beyond foundational central molecular biology dogma, stating inherited linear pieces of DNA transcribed to RNAs and translated into proteins. Crucially, over 95% genome, initially considered junk between genes, encodes essential, functionally diverse non-protein-coding RNAs, raising gene count at least one order magnitude. Most phenotype-determining changes regulatory areas control can directly or indirectly phenotypes regulating protein function, transferring information within organisms, generating DNA. also exhibit high structural, functional, biomolecular interaction plasticity modified via editing, methylation, glycosylation, other mechanisms, which bestow them with intra- extracellular functions without altering underlying is, therefore, currently primary determinant cellular populational functional diversity, disease-linked structural variations, cell function regulation. As demonstrated RNA-based coronavirus vaccines' success, technology is transforming medicine, agriculture, industry, as did advent recombinant 1980s.

Язык: Английский

Процитировано

0