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

et al.

Published: Nov. 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.

Language: Английский

GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia DOI Creative Commons
Lincoln MP Shade, Yuriko Katsumata, Erin L. Abner

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(11), P. 2407 - 2421

Published: Oct. 8, 2024

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous belie complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from following three sources: National Coordinating Center, Religious Orders Study Rush Memory Aging Project, Adult Changes Thought study (n = 7,804 total autopsied participants). We eight independent significantly associated loci, which four were new (COL4A1, PIK3R5, LZTS1 APOC2). Separately testing known ADRD 19 loci at least one after false-discovery rate adjustment. Genetic colocalization analyses pleiotropic effects quantitative trait Methylation cerebral cortex two sites near APOC2 was amyloid angiopathy. Studies that include are an important step understanding mechanisms risk. identify common variants distinct endophenotypes, providing insights into risk dementias.

Language: Английский

Citations

8
Systematic review and meta‐analysis of bulk RNAseq studies in human Alzheimer's disease brain tissue DOI Creative Commons
Bernardo Aguzzoli Heberle, Kevin Fox, Lucas Lobraico Libermann

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

We systematically reviewed and meta-analyzed bulk RNA sequencing (RNAseq) studies comparing Alzheimer's disease (AD) patients to controls in human brain tissue. searched PubMed, Web of Science, Scopus for RNAseq studies, excluding re-analyses limited small RNAs or gene panels. developed 10 criteria quality assessment performed a meta-analysis on three high-quality datasets. Of 3266 records, 24 qualified the systematic review, one study with datasets meta-analysis. The identified 571 differentially expressed genes (DEGs) temporal lobe 189 frontal lobe, including CLU GFAP. Pathway analysis suggested reactivation developmental processes adult AD brain. Limited data availability constrained These findings underscore need rigorous methods transcriptomic research better identify changes advance biomarker therapeutic development. This review is registered PROSPERO (CRD42023466522). Comprehensive review: Conducted first non-demented using primary Identified AD, revealing potential targets. discovery: Highlighted key overlapping pathways such as "tube morphogenesis" "neuroactive ligand-receptor interaction" that may play critical roles AD. Emphasized importance methodological rigor tools guide future Acknowledged access complete tables lack diversity existing datasets, which some analysis.

Language: Английский

Citations

0
Proteomic Subtyping of Alzheimer's Disease CSF links Blood-Brain Barrier Dysfunction to Reduced levels of Tau and Synaptic Biomarkers DOI Creative Commons
Madison C. Bangs, Joshna Gadhavi, Kathleen Carter

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 15, 2025

Abstract Alzheimer’s disease (AD) is characterized by significant clinical and molecular heterogeneity, influenced genetic demographic factors. Using an unbiased, network-driven approach, we analyzed the cerebrospinal fluid (CSF) proteome from 431 individuals (483 samples), including 111 African American participants, to identify core protein modules associated with AD, race, sex, age. Our analysis revealed ten co-expression linked distinct biological pathways cell types, many of which correlated established AD biomarkers such as β-amyloid, tau, phosphorylated tau. To further resolve applied a proteomic subtyping identifying six CSF subtypes spanning pathological spectrum. These were validated across independent cohorts, aligning previously defined subtypes, those neuronal hyperplasticity, immune activation, blood-brain barrier (BBB) integrity. Notably, BBB subtype, enriched Americans men, was low high CSF/serum albumin ratios, reduced synaptic levels. This subtype also exhibited increased levels proteolytic enzymes, thrombin matrix metalloproteases, that cleave Plasma dilution into hyperplastic led tau module levels, indicating plasma protease activity contributes depletion underlying brain pathology. findings highlight impact integrity on particularly in men Americans, underscore need for diversity-informed biomarker strategies improve diagnostics therapeutic targeting populations.

Language: Английский

Citations

0
Transcriptomics in the era of long-read sequencing DOI Creative Commons
Carolina Monzó, Tianyuan Liu, Ana Conesa

et al.

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Language: Английский

Citations

0
The Regulation of Frontal Cortex Cholesterol Metabolism Abnormalities by NR3C1/NRIP1/NR1H2 Is Involved in the Occurrence of Stress-Induced Depression DOI Open Access

Rui Shi,

Yingmin Li,

Weihao Zhu

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8075 - 8075

Published: July 24, 2024

Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of neurons associated with specific molecular mechanisms remain unclear. This study initially analyzed relationship between cholesterol using NHANES database. We then induced depressive-like behaviors mice via restraint stress. Applying bioinformatics, pathology, biology, we observed pathological characteristics brain homeostasis investigated regulatory disorders. Through database, confirmed a significant correlation abnormalities depression. Furthermore, based on successful stress mouse model establishment, discovered number cholesterol-related DEGs significantly increased due stress, exhibited regional heterogeneity. Further investigation frontal cortex, region closely related depression, revealed caused disruption key genes metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, LDLR, leading an increase total content decrease synaptic proteins PSD-95 SYN. indicates affects neuronal plasticity is stress-induced behavior mice. Adeno-associated virus interference NR3C1 prefrontal cortex subjected short-term resulted reduced protein levels NRIP1, NR1H2, content. At same time, it PSD95 SYN, effectively alleviating behavior. Therefore, these results suggest that may induce disorders by activating NR3C1/NRIP1/NR1H2 signaling pathway. impairs consequently participates These findings abnormal contributor

Language: Английский

Citations

1
Multiple Transcriptomic Analyses Explore Potential Synaptic Biomarker Rabphilin-3A for Alzheimer's Disease DOI Creative Commons
Doan Phuong Quy Nguyen, Son Pham, Amadou Wurry Jallow

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 12, 2024

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder afflicting the elderly population worldwide. The identification of potential gene candidates for AD holds promises diagnostic biomarkers and therapeutic targets. Employing comprehensive strategy, this study integrated transcriptomic data from diverse sources, including microarray single-cell datasets blood tissue samples, enabling detailed exploration expression dynamics. Through thorough investigation, 19 notable candidate genes were found with consistent changes across both datasets, suggesting their as AD. In addition, single cell sequencing analysis further highlighted specific in excitatory inhibitory neurons, primary functional units brain, underscoring relevance to pathology. Moreover, enrichment revealed that three downregulated synaptic signaling pathway. Further validation experiments significantly showed reduced levels rabphilin-3A (RPH3A) 3xTg-AD model mice, implying its role pathogenesis. Given neurotransmitter exocytosis function, investigation into RPH3A interactions neurotrophic proteins may provide valuable insights complex molecular mechanisms underlying dysfunction

Language: Английский

Citations

1
Scywalker: Scalable end-to-end data analysis workflow for long-read single-cell transcriptome sequencing DOI Creative Commons
Peter De Rijk, Tijs Watzeels, Fahri Küçükali

et al.

Bioinformatics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Existing nanopore single-cell data analysis tools showed severe limitations in handling current sizes.

Language: Английский

Citations

1
Long-read RNA sequencing: a transformative technology for exploring transcriptome complexity in human diseases DOI Creative Commons

Isabelle Heifetz Ament,

Nicole DeBruyne,

Feng Wang

et al.

Molecular Therapy, Journal Year: 2024, Volume and Issue: 33(3), P. 883 - 894

Published: Nov. 19, 2024

Long-read RNA sequencing (RNA-seq) is emerging as a powerful and versatile technology for studying human transcriptomes. By enabling the end-to-end of full-length transcripts, long-read RNA-seq opens up avenues investigating various species features that cannot be reliably interrogated by standard short-read methods. In this review, we present an overview RNA-seq, delineating its strengths over well summarizing recent advances in experimental computational approaches to boost power long-read-based transcriptomics. We describe wide range applications highlight expanding role foundational exploring transcriptome variations diseases.

Language: Английский

Citations

1
Unraveling aging from transcriptomics DOI
Yuanfang Huang, Sheng Zhu, Shuai Yao

et al.

Trends in Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

Citations

0
Isoform-level expression of the constitutive androstane receptor (CAR or NR1I3) transcription factor better predicts the mRNA expression of the cytochrome P450s in human liver samples DOI Open Access

Joseph M. Collins,

Daqing Wang

Drug Metabolism and Disposition, Journal Year: 2024, Volume and Issue: 53(1), P. 100011 - 100011

Published: Oct. 21, 2024

Many factors cause interperson variability in the activity and expression of cytochrome P450 (CYP) drug-metabolizing enzymes liver, leading to variable drug exposure treatment outcomes. Several liver-enriched transcription are associated with CYP expression, estrogen receptor α (ESR1) constitutive androstane (CAR or NR1I3) being 2 top factors. ESR1 NR1I3 undergo extensive alternative splicing that results numerous splice isoforms, but how these isoforms associate is unknown. Here, we quantified 18 3 most abundant 260 liver samples derived from African Americans (n = 125) European 135). Our showed isoform populations for both ESR1. Multiple linear regression analyses revealed compared gene-level NR1I3, isoform-level better predicted mRNA CYPs UDP-glucuronosyltransferases (UGTs), whereas improved predictive models UGTs CYP2D6 not CYPs. Also, different were CYPs, associations varied depending on sample ancestry. Surprisingly, noncanonical having retained introns (introns 6) abundantly expressed UGTs, reference (NR1I3-205) was only CYP2D6. Moreover, diversity increased during differentiation induced pluripotent stem cells hepatocytes, paralleling increasing expression. These suggest factor may help explain variation UGT between individuals. SIGNIFICANCE STATEMENT: We American donors found liver. analysis that, some P450s UDP-glucuronosyltransferases, highlighting importance enhance our understanding gene transcriptional regulatory networks controlling enzymes.

Language: Английский

Citations

0