snoRNAs: functions and mechanisms in biological processes, and roles in tumor pathophysiology

Cell Death Discovery, Год журнала: 2022, Номер 8(1)

Опубликована: Май 12, 2022

Small nucleolar RNAs (snoRNAs), a type of non-coding RNA, are widely present in the nucleoli eukaryotic cells and play an important role rRNA modification. With recent increase research on snoRNAs, new evidence has emerged indicating that snoRNAs also participate tRNA mRNA Studies suggest numerous including tumor-promoting tumor-suppressing not only dysregulated tumors but show associations with clinical prognosis. In this review, we summarize reported functions possible mechanisms underlying their tumorigenesis cancer development to guide snoRNA-based diagnosis treatment future.

Язык: Английский

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Single-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue

Nature Biotechnology, Год журнала: 2022, Номер 40(7), С. 1082 - 1092

Опубликована: Март 7, 2022

Abstract Single-nuclei RNA sequencing characterizes cell types at the gene level. However, compared to single-cell approaches, many single-nuclei cDNAs are purely intronic, lack barcodes and hinder study of isoforms. Here we present isoform (SnISOr-Seq). Using microfluidics, PCR-based artifact removal, target enrichment long-read sequencing, SnISOr-Seq increased barcoded, exon-spanning long reads 7.5-fold naive sequencing. We applied adult human frontal cortex found that exons associated with autism exhibit coordinated highly cell-type-specific inclusion. two distinct combination patterns: those distinguishing neural types, enriched in TSS-exon, exon-polyadenylation-site non-adjacent exon pairs, multiple configurations within one type, adjacent pairs. Finally, observed human-specific almost as tightly conserved exons, implying coordination can be rapidly established during evolution. enables analysis brain any frozen or hard-to-dissociate sample.

Язык: Английский

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Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, role of cell type-specific transcript-isoform diversity during human development not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing deeply profile full-length transcriptome germinal zone cortical plate regions developing neocortex at tissue single-cell resolution. We identified 214,516 distinct isoforms, which 72.6% were novel (not previously annotated Gencode version 33), uncovered a substantial contribution diversity-regulated by binding proteins-in defining cellular identity neocortex. comprehensive isoform-centric gene annotation reprioritize thousands rare de novo risk variants elucidate genetic mechanisms for disorders.

Язык: Английский

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Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain

Nature Genetics, Год журнала: 2023, Номер 55(12), С. 2117 - 2128

Опубликована: Ноя. 30, 2023

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as molecular outcome measure. This challenge is particularly relevant for the brain, which extensive splicing generates multiple distinct transcript-isoforms per gene. Due complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, multivariate, stepwise framework genetics, phenotypic associations. Compared gene-level methods, isoTWAS improves both isoform prediction, yielding more testable genes, increased power discovery trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate undetectable gene-level, prioritizing isoforms AKT3, CUL3 HSPD1 schizophrenia PCLO disorders. Results highlight importance incorporating resolution integrative approaches increase associations, especially brain-relevant

Язык: Английский

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IsoTools: a flexible workflow for long-read transcriptome sequencing analysis

Bioinformatics, Год журнала: 2023, Номер 39(6)

Опубликована: Июнь 1, 2023

Long-read transcriptome sequencing (LRTS) has the potential to enhance our understanding of alternative splicing and complexity this process requires use versatile computational tools, with ability accommodate various stages workflow maximum flexibility.

Язык: Английский

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A single-cell multi-omic atlas spanning the adult rhesus macaque brain

Science Advances, Год журнала: 2023, Номер 9(41)

Опубликована: Окт. 12, 2023

Cataloging the diverse cellular architecture of primate brain is crucial for understanding cognition, behavior, and disease in humans. Here, we generated a brain-wide single-cell multimodal molecular atlas rhesus macaque brain. Together, profiled 2.58 M transcriptomes 1.59 epigenomes from single nuclei sampled 30 regions across adult Cell composition differed extensively brain, revealing signatures region-specific functions. We also identified 1.19 candidate regulatory elements, many previously unidentified, allowing us to explore landscape cis-regulatory grammar neurological risk cell type–specific manner. Altogether, this multi-omic provides an open resource investigating evolution human identifying novel targets interventions.

Язык: Английский

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Random genetic drift sets an upper limit on mRNA splicing accuracy in metazoans

eLife, Год журнала: 2024, Номер 13

Опубликована: Янв. 18, 2024

Most eukaryotic genes undergo alternative splicing (AS), but the overall functional significance of this process remains a controversial issue. It has been noticed that complexity organisms (assayed by number distinct cell types) correlates positively with their genome-wide AS rate. This interpreted as evidence plays an important role in adaptive evolution increasing repertoires genomes. However, observation also fits totally opposite interpretation: given ‘complex’ tend to have small effective population sizes ( Ne ), they are expected be more affected genetic drift, and hence prone accumulate deleterious mutations decrease accuracy. Thus, according ‘drift barrier’ theory, elevated rate complex might simply result from higher error To test hypothesis, we analyzed 3496 transcriptome sequencing samples quantify 53 metazoan species spanning wide range values. Our results show negative correlation between proxies rates among species, consistent drift barrier hypothesis. pattern is dominated low abundance isoforms, which represent vast majority splice variant repertoire. We these isoforms depleted events, most likely correspond errors. Conversely, abundant relatively enriched tends lower species. All observations hypothesis variation across metazoans reflects limits set on capacity selection prevent gene expression

Язык: Английский

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Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq

Nature Biotechnology, Год журнала: 2024, Номер unknown

Опубликована: Май 22, 2024

Abstract Determining whether the RNA isoforms from medically relevant genes have distinct functions could facilitate direct targeting of for disease treatment. Here, as a step toward this goal neurological diseases, we sequenced 12 postmortem, aged human frontal cortices (6 Alzheimer cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. We identified 1,917 expressing multiple in cortex where 1,018 had with different protein-coding sequences. Of these genes, 57 are implicated brain-related diseases including major depression, schizophrenia, Parkinson’s disease. Our study also uncovered 53 new several isoform was most highly expressed that gene. reported on five mitochondrially encoded, spliced isoforms. found 99 differentially between controls.

Язык: Английский

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Identification of region-specific gene isoforms in the human brain using long-read transcriptome sequencing

Science Advances, Год журнала: 2024, Номер 10(4)

Опубликована: Янв. 24, 2024

In neurological and neuropsychiatric diseases, different brain regions are affected, differences in gene expression patterns could potentially explain this mechanism. However, limited studies have precisely explored of the human brain. study, we performed long-read RNA sequencing on three same individuals: cerebellum, hypothalamus, temporal cortex. Despite stringent filtering criteria excluding isoforms predicted to be artifacts, over half expressed multiple samples across were found unregistered GENCODE reference. We then especially focused genes with major each region, even similar overall levels, identified that many such including GAS7 might distinct roles dendritic spine neuronal formation region. also DNA methylation might, part, drive isoform expressions regions. These findings highlight significance analyzing disease-relevant sites.

Язык: Английский

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The Neurodiversity Framework in Medicine: On the Spectrum

Developmental Neurobiology, Год журнала: 2025, Номер 85(1)

Опубликована: Янв. 1, 2025

ABSTRACT The term “neurodiversity” refers to the natural heterogeneity in human neurological functioning, which includes neurodevelopmental differences and other mental health conditions (e.g., autism spectrum disorder [ASD], attention‐deficit hyperactivity [ADHD], dyslexia, bipolar disorder, schizophrenia, depression). This new viewpoint has significant consequences for future of medicine, specifically psychiatry, neurology, as it undermines established notions these disorders/diseases that may be healed or corrected. neurodiversity approach, on hand, acknowledges divergences variations, calling tailored support interventions accommodate individual needs. Neurodiversity could impact current medical perspectives by supporting a shift from pathology identity. Rather than focusing difficulties associated with specific ailment, approach stresses strengths distinct come neurodivergent identities. research therapy fostering development innovative treatments aimed at increasing quality life improving functional results. perspective advocates including people all sectors society, research, clinical practice, policymaking, recognizing, accepting, integrating variances brain functioning. In this article, we review movement propose “The Framework Medicine,” challenges traditional views recognizing advocating inclusive, person‐centered approaches healthcare.

Язык: Английский

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