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Research: Alternative splicing generates HER2 isoform diversity underlying antibody–drug conjugate resistance in breast cancer
- Gabriela D.A. Guardia,
- Carlos H. dos Anjos,
- Aline Rangel-Pozzo,
- Filipe F. dos Santos,
- Alexander Birbrair,
- Paula F. Asprino,
- Anamaria A. Camargo,
- and Pedro A.F. Galante
Genome Res. September 2025 35: 1942-1958; Published in Advance July 15, 2025, doi:10.1101/gr.280304.124
...reveal how alternative splicing events may alter receptor conformation, ligand binding, dimerization, and downstream signaling capabilities. However, experimental determination of protein structures, especially for multiple isoforms, is time-consuming, expensive, and often challenging. The advent...
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Research: Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids
- Benjamin D. Umans and
- Yoav Gilad
Genome Res. August 2025 35: 1689-1700; Published in Advance June 2, 2025, doi:10.1101/gr.280219.124
...an alternative to fixed-category classification of cell states, allowing for cells to be described quantitatively by multiple gene expression programs. To alleviate the computational burden of topic model estimation and downstream analysis, single-cell data were first aggregated into 10,707 “pseudocells...
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Research: A gene regulatory element modulates myosin expression and controls cardiomyocyte response to stress
- Taylor Anglen,
- Irene M. Kaplow,
- Baekgyu Choi,
- Enya Dewars,
- Robin M. Perelli,
- Kevin T. Hagy,
- Duc Tran,
- Megan E. Ramaker,
- Svati H. Shah,
- Inkyung Jung,
- Andrew P. Landstrom,
- Ravi Karra,
- Yarui Diao,
- and Charles A. Gersbach
Genome Res. November 2025 35: 2418-2432; Published in Advance October 22, 2025, doi:10.1101/gr.280825.125
...Wig files were used; if multiple replicates were available, pooled reads from across all replicates were used for the bigWig files. Human cell type–specific ATAC-seq signals from single-nucleus ATAC-seq data were taken from the Cardiac Atlas of Regulatory Elements (CARE) portal (Hocker et al. 2021). TF...
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Method: Assessing conservation of alternative splicing with evolutionary splicing graphs
- Diego Javier Zea,
- Sofya Laskina,
- Alexis Baudin,
- Hugues Richard,
- and Elodie Laine
Genome Res. August 2021 31: 1462-1473; Published in Advance June 15, 2021, doi:10.1101/gr.274696.120
...AS eventsWe tested ThorAxe on a curated set of 50 genes representing 16 families (Supplemental Table S1; Supplemental Methods), in which several splice variants have been associated with diverse protein functions. ThorAxe detected 448 alternative splicing, initiation, and termination events. RNA-seq splice...
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Method: Biosurfer for systematic tracking of regulatory mechanisms leading to protein isoform diversity
- Mayank Murali,
- Jamie Saquing,
- Senbao Lu,
- Ziyang Gao,
- Emily F. Watts,
- Ben Jordan,
- Zachary Peters Wakefield,
- Ana Fiszbein,
- David R. Cooper,
- Peter J. Castaldi,
- Dmitry Korkin,
- and Gloria M. Sheynkman
Genome Res. April 2025 35: 1012-1024; Published in Advance March 14, 2025, doi:10.1101/gr.279317.124
...of the functional role of protein isoforms, providing mechanistic explanation of the origins of the proteomic diversity driven by the AS. Biosurfer is available as a Python package.Through mechanisms of alternative transcription, splicing, and polyadenylation, nearly every human gene can produce multiple protein...
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Research: Global regulatory features of alternative splicing across tissues and within the nervous system of C. elegans
- Bina Koterniak,
- Pallavi P. Pilaka,
- Xicotencatl Gracida,
- Lisa-Marie Schneider,
- Iva Pritišanac,
- Yun Zhang,
- and John A. Calarco
Genome Res. December 2020 30: 1766-1780; Published in Advance October 30, 2020, doi:10.1101/gr.267328.120
...that neuronal-subtype differences in splicing have been interrogated and have revealed differences in isoform expression (Wamsley et al. 2018; Wang et al. 2018; Furlanis et al. 2019; Saito et al. 2019). Taken together, these observations and our own results suggest that an expanded use of alternative splicing...
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Method: Long-read RNA sequencing reveals allele-specific N⁶-methyladenosine modifications
- Dayea Park and
- Can Cenik
Genome Res. April 2025 35: 999-1011; Published in Advance October 29, 2024, doi:10.1101/gr.279270.124
...RNA stability, or alternative splicing between the alleles due to genetic variation (Nembaware et al. 2008; Pai et al. 2012; Amoah et al. 2021). That is, local genetic variants can influence transcriptional or posttranscriptional processes to modulate the mRNA abundance of each allele (Robles-Espinoza et al...
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Method: Native molecule sequencing by nano-ID reveals synthesis and stability of RNA isoforms
- Kerstin C. Maier,
- Saskia Gressel,
- Patrick Cramer,
- and Björn Schwalb
Genome Res. September 2020 30: 1332-1344; Published in Advance September 4, 2020, doi:10.1101/gr.257857.119
.... 2016; Turner et al. 2018). In addition, alternative splicing results in RNA isoforms that differ in the composition of their RNA body (Tilgner et al. 2015; Garalde et al. 2018). Different mRNA isoforms can result in functionally different proteins. Vulnerabilities in splicing can lead to nonfunctional...
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Resource: Genome-wide identification of tandem repeats associated with splicing variation across 49 tissues in humans
- Kohei Hamanaka,
- Daisuke Yamauchi,
- Eriko Koshimizu,
- Kei Watase,
- Kaoru Mogushi,
- Kinya Ishikawa,
- Hidehiro Mizusawa,
- Naomi Tsuchida,
- Yuri Uchiyama,
- Atsushi Fujita,
- Kazuharu Misawa,
- Takeshi Mizuguchi,
- Satoko Miyatake,
- and Naomichi Matsumoto
Genome Res. March 2023 33: 435-447; Published in Advance March 27, 2023, doi:10.1101/gr.277335.122
...pairs of each gene (Fig. 1A), only the top association in the linear regression was considered, and its P-value was adjusted for all TR–splicing pairs in each gene by employing a FastQTL permutation scheme. The adjusted P-values were further corrected for multiple gene testing by the Benjamini...
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Research: Sense–antisense miRNA pairs constitute an elaborate reciprocal regulatory circuit
- Yulong Song,
- Lishi Li,
- Wenbing Yang,
- Qiang Fu,
- Wanying Chen,
- Zeng Fang,
- Wen Li,
- Nannan Gu,
- and Rui Zhang
Genome Res. May 2020 30: 661-672; Published in Advance May 18, 2020, doi:10.1101/gr.257121.119
...) three histone marks associated with regulatory elements and promoter from the ENCODE. (B–D) RNA expression of miRNA-ATs (B), sense-mature miRNAs (C), and sense pri-miRNAs (D) in HEK293T cells transfected simultaneously with four gRNAs targeting the indicated miRNA-ATs along with the dCas9-activator...

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