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1.
Cell Rep Methods ; 4(3): 100736, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38508189

RESUMO

Differential transcript usage (DTU) plays a crucial role in determining how gene expression differs among cells, tissues, and developmental stages, contributing to the complexity and diversity of biological systems. In abnormal cells, it can also lead to deficiencies in protein function and underpin disease pathogenesis. Analyzing DTU via RNA sequencing (RNA-seq) data is vital, but the genetic heterogeneity in populations with complex diseases presents an intricate challenge due to diverse causal events and undetermined subtypes. Although the majority of common diseases in humans are categorized as complex, state-of-the-art DTU analysis methods often overlook this heterogeneity in their models. We therefore developed SPIT, a statistical tool that identifies predominant subgroups in transcript usage within a population along with their distinctive sets of DTU events. This study provides comprehensive assessments of SPIT's methodology and applies it to analyze brain samples from individuals with schizophrenia, revealing previously unreported DTU events in six candidate genes.


Assuntos
Perfilação da Expressão Gênica , RNA , Humanos , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA
2.
Nat Comput Sci ; 3(8): 700-708, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38098813

RESUMO

ORFanage is a system designed to assign open reading frames (ORFs) to known and novel gene transcripts while maximizing similarity to annotated proteins. The primary intended use of ORFanage is the identification of ORFs in the assembled results of RNA sequencing experiments, a capability that most transcriptome assembly methods do not have. Our experiments demonstrate how ORFanage can be used to find novel protein variants in RNA-seq datasets, and to improve the annotations of ORFs in tens of thousands of transcript models in the human annotation databases. Through its implementation of a highly accurate and efficient pseudo-alignment algorithm, ORFanage is substantially faster than other ORF annotation methods, enabling its application to very large datasets. When used to analyze transcriptome assemblies, ORFanage can aid in the separation of signal from transcriptional noise and the identification of likely functional transcript variants, ultimately advancing our understanding of biology and medicine.

3.
Genome Biol ; 24(1): 249, 2023 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-37904256

RESUMO

CHESS 3 represents an improved human gene catalog based on nearly 10,000 RNA-seq experiments across 54 body sites. It significantly improves current genome annotation by integrating the latest reference data and algorithms, machine learning techniques for noise filtering, and new protein structure prediction methods. CHESS 3 contains 41,356 genes, including 19,839 protein-coding genes and 158,377 transcripts, with 14,863 protein-coding transcripts not in other catalogs. It includes all MANE transcripts and at least one transcript for most RefSeq and GENCODE genes. On the CHM13 human genome, the CHESS 3 catalog contains an additional 129 protein-coding genes. CHESS 3 is available at http://ccb.jhu.edu/chess .


Assuntos
Genoma Humano , Proteínas , Humanos , Filogenia , Proteínas/genética , Algoritmos , Software , Anotação de Sequência Molecular
4.
bioRxiv ; 2023 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-37503064

RESUMO

Differential transcript usage (DTU) plays a crucial role in determining how gene expression differs among cells, tissues, and different developmental stages, thereby contributing to the complexity and diversity of biological systems. In abnormal cells, it can also lead to deficiencies in protein function, potentially leading to pathogenesis of diseases. Detecting such events for single-gene genetic traits is relatively uncomplicated; however, the heterogeneity of populations with complex diseases presents an intricate challenge due to the presence of diverse causal events and undetermined subtypes. SPIT is the first statistical tool that quantifies the heterogeneity in transcript usage within a population and identifies predominant subgroups along with their distinctive sets of DTU events. We provide comprehensive assessments of SPIT's methodology in both single-gene and complex traits and report the results of applying SPIT to analyze brain samples from individuals with schizophrenia. Our analysis reveals previously unreported DTU events in six candidate genes.

5.
bioRxiv ; 2023 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-36993373

RESUMO

ORFanage is a system designed to assign open reading frames (ORFs) to both known and novel gene transcripts while maximizing similarity to annotated proteins. The primary intended use of ORFanage is the identification of ORFs in the assembled results of RNA sequencing (RNA-seq) experiments, a capability that most transcriptome assembly methods do not have. Our experiments demonstrate how ORFanage can be used to find novel protein variants in RNA-seq datasets, and to improve the annotations of ORFs in tens of thousands of transcript models in the RefSeq and GENCODE human annotation databases. Through its implementation of a highly accurate and efficient pseudo-alignment algorithm, ORFanage is substantially faster than other ORF annotation methods, enabling its application to very large datasets. When used to analyze transcriptome assemblies, ORFanage can aid in the separation of signal from transcriptional noise and the identification of likely functional transcript variants, ultimately advancing our understanding of biology and medicine.

6.
Sci Adv ; 8(25): eabn3471, 2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35731869

RESUMO

Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-line interventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to target guanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We report that TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Last, we show that the G4 and RNA binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , DNA/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/metabolismo , Guanina/farmacologia , Humanos , Mutação , RNA , Temozolomida/farmacologia , Temozolomida/uso terapêutico
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