Molecular basis of the CYFIP2 and NCKAP1 autism‐linked variants in the WAVE regulatory complex DOI Creative Commons
Song Xie, Ke Zuo, Silvia De Rubeis

и другие.

Protein Science, Год журнала: 2024, Номер 34(1)

Опубликована: Дек. 11, 2024

The WAVE regulatory pentameric complex regulates actin remodeling. Two components of it (CYFIP2 and NCKAP1) are encoded by genes whose genetic mutations increase the risk for autism spectrum disorder (ASD) related neurodevelopmental disorders. Here, we use a newly developed computational protocol hotspot analysis to uncover functional impact these at interface correct isoforms two proteins into complex. turn out be located on surfaces involving largest number hotspots Most them decrease affinity rest complex, but some have opposite effect. results fully consistent with available experimental data. observed changes in stability might activation ultimately play role aberrant pathway leading cell derangement associated disease.

Язык: Английский

ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3 DOI Creative Commons
Isabella Lin, Zain Awamleh,

Mili Sinvhal

и другие.

BMC Medical Genomics, Год журнала: 2024, Номер 17(1)

Опубликована: Ноя. 29, 2024

Abstract Background Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified both pediatric neurodevelopmental syndromes and as somatic cancer. However, little is known about the extent shared disruption signaling pathways by same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 ( ASXL1 ), where truncating heterozygous cause Bohring-Opitz syndrome (BOS, OMIM #605039), germline disorder, while driver events acute myeloid leukemia (AML). No BOS patients have been reported to AML. Methods This explores common dysregulated with We analyzed whole blood transcriptomic DNA methylation data from AML -variant (AML- ) examined differential exon usage cell proportions. Results Our analyses molecular signatures between AML- highlighted key biomarkers, including VANGL2 , GRIK5 GREM2 samples variants, regardless disease type. Notably, our revealed significant de-repression posterior homeobox A HOXA upregulation Wnt-signaling hematopoietic regulator HOXB4 . While discovered many features, also splice isoforms RUNX3 long isoform, p46, preferentially expressed BOS, shorter p44 isoform ASXL1. Conclusion findings highlight strong effects supersede cell-type even states. first direct comparison profiles driven pathogenic modifier gene distinct Similar RASopathies, which lead overlapping phenotypes can be treated inhibiting pathway, identifies for targeted Comparative approaches high-penetrance genetic types states identify targetable treat multiple Finally, work highlights connections epigenes, such underlying stem-cell state early development malignancy.

Язык: Английский

Процитировано

2
RNA structure in alternative splicing regulation: from mechanism to therapy DOI Creative Commons

Nengcheng Bao,

Zhechao Wang,

Jiayan Fu

и другие.

Acta Biochimica et Biophysica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Июль 1, 2024

Alternative splicing is a highly intricate process that plays crucial role in post-transcriptional regulation and significantly expands the functional proteome of limited number coding genes eukaryotes. Its multifactorial, with RNA structure exerting significant impact. Aberrant conformations lead to dysregulation patterns, which directly affects manifestation disease symptoms. In this review, molecular mechanisms secondary structure-mediated are summarized, focus on complex interplay between aberrant phenotypes resulted from defects. This study also explores additional factors reshape structural conformations, enriching our understanding mechanistic network underlying regulation. addition, an emphasis has been placed clinical targeting corrections human diseases. The principal action behind phenomenon described, followed by discussion prospective development strategies pertinent challenges.

Язык: Английский

Процитировано

2
Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes DOI Creative Commons
Xiaona Lu, Pengyu Ni, Paola Suárez-Meade

и другие.

Cell Reports, Год журнала: 2024, Номер 43(7), С. 114376 - 114376

Опубликована: Июнь 19, 2024

Precision of transcription is critical because transcriptional dysregulation disease causing. Traditional methods profiling are inadequate to elucidate the full spectrum transcriptome, particularly for longer and less abundant mRNAs. SHANK3 one most common autism causative genes. Twenty-four Shank3-mutant animal lines have been developed modeling. However, their preclinical validity has questioned due incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture long-read sequencing profile transcriptome in humans mice. unexpectedly discover extremely complex transcriptome. Specific transcripts altered mice postmortem brain tissues from individuals with disorder. The enhanced significantly improves detection rate potential deleterious variants genomics studies neuropsychiatric disorders. Our findings suggest that both deterministic stochastic genome associated SHANK family

Язык: Английский

Процитировано

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

и другие.

Molecular Therapy, Год журнала: 2024, Номер 33(3), С. 883 - 894

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

1
Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model DOI Creative Commons
Emma F. Jones, Timothy C. Howton, Tabea M. Soelter

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 29, 2024

Abstract Schinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in the SETBP1 gene. While previous studies determined multiple roles for how and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role SGS. We used STARsolo to quantify gene splice junction (SJ) expression 51,465 nuclei previously generated from cerebral cortex of atypical Setbp1 S858R SGS patient variant mice (n = 3) wild-type control 3). After cell type annotation, we performed pseudobulk differential SJ usage (SJU) analyses across types conditions. identified 34 genes with statistically significant alterations SJU. Oligodendrocytes had most changes SJU, followed astrocytes, excitatory, inhibitory neurons. One gene, Son , cofactor known neurodevelopmental ZTTK Syndrome, SJU all six non-vascular measured compared controls. This first research report AS model study link perturbations .

Язык: Английский

Процитировано

0
Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis DOI

Nil Aygün,

Celine K. Vuong,

Oleh Krupa

и другие.

The American Journal of Human Genetics, Год журнала: 2024, Номер 111(9), С. 1877 - 1898

Опубликована: Авг. 20, 2024

Язык: Английский

Процитировано

0
SQANTI-reads: a tool for the quality assessment of long read data in multi-sample lrRNA-seq experiments. DOI Creative Commons
Netanya Keil, Carolina Monzó, Lauren M. McIntyre

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 25, 2024

ABSTRACT SQANTI-reads leverages SQANTI3, a tool for the analysis of quality transcript models, to develop read-level control framework replicated long-read RNA-seq experiments. The number and distribution reads, as well unique junction chains (transcript splicing patterns), in SQANTI3 structural categories are informative raw data quality. Multi-sample visualizations QC metrics presented by experimental design factors identify outliers. We introduce new 1) identification potentially under-annotated genes putative novel transcripts 2) quantifying variation donors acceptors. applied two different datasets, Drosophila developmental experiment multi-platform dataset from LRGASP project demonstrate that effectively reveals impact read coverage on quality, readily identifies strong weak sites. is open source available download at GitHub.

Язык: Английский

Процитировано

0
Unveiling RNA isoform diversity in the brain using long-read RNA sequencing DOI
Kazuki Nagayasu

Folia Pharmacologica Japonica, Год журнала: 2024, Номер 159(5), С. 342 - 342

Опубликована: Авг. 31, 2024

Язык: Английский

Процитировано

0
Human-derived monoclonal autoantibodies as interrogators of cellular proteotypes in the brain DOI Creative Commons
Matthew L. Baum, Christopher M. Bartley

Trends in Neurosciences, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

Процитировано

0
Deciphering the Cell-Specific Transcript Heterogeneity and Alternative Splicing during the Early Embryonic Development of Zebrafish DOI Creative Commons
Xiumei Lin, Xue Wang, Chang Liu

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 8, 2024

Abstract Cell fate determination during early embryonic development is a complex process modulated by gene expression. The intricate interplay of transcriptional and post-transcriptional regulation integral to the developmental trajectory embryogenesis, yet how RNA processing may contribute programming largely elusive. Leveraging recent technological advances in single-molecule nanopore sequencing, we developed single-cell long-read transcriptome sequencing technology, allowing clear view transcript diversity zebrafish embryogenesis pre- post-zygotic genome activation (ZGA). A closer examination dynamic usage potential alternative splicing revealed that abundant stage-specific transcripts with differential coding potentials are involved distinct biological functions. Specifically, identified two cell populations at onset ZGA based on isoform instead profiling, which followed divergent trajectories toward ectoderm presumptive ectoderm. These cells were characterized regulations linked RNA-binding proteins, including SNRPA SFPQ. Altogether, using strategy, work has cell-specific dynamics contributing embryogenesis.

Язык: Английский

Процитировано

0