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

Bernardo Aguzzoli Heberle; J. Anthony Brandon; Madeline L. Page; Kayla A. Nations; Ketsile I. Dikobe; Brendan J. White; Lacey A. Gordon; Grant A. Fox; Mark E. Wadsworth; Patricia H. Doyle; Brittney A. Williams; Edward J. Fox; Anantharaman Shantaraman; Mina Ryten; Sara Goodwin; Elena Ghiban; Robert Wappel; Senem Mavruk-Eskipehlivan; Justin B. Miller; Nicholas T. Seyfried; Peter T. Nelson; John D. Fryer; Mark T.W. Ebbert

doi:10.1038/s41587-024-02245-9

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

Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Kayla A. Nations, Ketsile I. Dikobe, Brendan J. White, Lacey A. Gordon, Grant A. Fox, Mark E. Wadsworth, Patricia H. Doyle, Brittney A. Williams, Edward J. Fox, Anantharaman Shantaraman, Mina Ryten, Sara Goodwin, Elena Ghiban, Robert Wappel, Senem Mavruk-Eskipehlivan, Justin B. Miller, Nicholas T. SeyfriedPeter T. Nelson, John D. Fryer, Mark T.W. Ebbert

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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

Original language	English
Article number	177
Pages (from-to)	635-646
Number of pages	12
Journal	Nature Biotechnology
Volume	43
Issue number	4
DOIs	https://doi.org/10.1038/s41587-024-02245-9
State	Published - Apr 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

This work was supported by: the National Institutes of Health (NIH; grant nos. R35GM138636, R01AG068331 to M.T.W.E. and 5R50CA243890 to S.G.); the BrightFocus Foundation (grant no. A2020161S to M.T.W.E.), Alzheimer’s Association (grant no. 2019-AARG-644082 to M.T.W.E.), PhRMA Foundation (grant no. RSGTMT17 to M.T.W.E.); the Ed and Ethel Moore Alzheimer’s Disease Research Program of Florida Department of Health (grant nos. 8AZ10 and 9AZ08 to M.T.W.E. and 6AZ06 to J.D.F.); and the Muscular Dystrophy Association (to M.T.W.E.). We appreciate the contributions of the Sanders-Brown Center on Aging at the University of Kentucky. We are deeply grateful to the research participants and their families who made this research possible. We thank S. L. Anderson from the University of Kentucky brain bank for preparing the brain samples used in the present study. We thank the University of Kentucky Center for Computational Sciences and Information Technology Services Research Computing for their support and use of the Morgan Compute Cluster and associated research computing resources. We thank Singularity Sylabs for providing support and extra cloud storage for our software containers. We are grateful for support from the Goeke lab members who quickly and thoroughly answered our numerous questions about bambu on GitHub. We thank T. Wendt Viola, R. Grassi-Oliveira and C. Walss-Bass for guidance and help in the early stages of the proteomics analysis. We thank the reviewers for their sincere and meaningful contributions to improving the quality of the manuscript. The results published in the present study are in part based on data obtained from the AD Knowledge Portal. Short-read RNA-seq data used for crossvalidation of results in the present study were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Rush Alzheimer’s Disease Center data collection was supported through funding by National Institute on Aging (grant nos. P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP) and RC2AG0365 (RNA-seq)).

Funders	Funder number
RNA-seq
Muscular Dystrophy Association
BrightFocus Foundation	A2020161S
National Institute on Aging	RC2AG0365, P30AG10161, R01AG17917, R01AG15819
Alzheimer's Association	2019-AARG-644082
Pharmaceutical Research and Manufacturers of America Foundation	RSGTMT17
National Institutes of Health (NIH)	5R50CA243890, R35GM138636, R01AG068331
Ed and Ethel Moore Alzheimer’s Disease Research Program of Florida Department of Health	6AZ06, 8AZ10, 9AZ08

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Biomedical Engineering
Molecular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41587-024-02245-9

Cite this

Aguzzoli Heberle, B., Brandon, J. A., Page, M. L., Nations, K. A., Dikobe, K. I., White, B. J., Gordon, L. A., Fox, G. A., Wadsworth, M. E., Doyle, P. H., Williams, B. A., Fox, E. J., Shantaraman, A., Ryten, M., Goodwin, S., Ghiban, E., Wappel, R., Mavruk-Eskipehlivan, S., Miller, J. B., ... Ebbert, M. T. W. (2025). Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq. Nature Biotechnology, 43(4), 635-646. Article 177. https://doi.org/10.1038/s41587-024-02245-9

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Aguzzoli Heberle, B, Brandon, JA, Page, ML, Nations, KA, Dikobe, KI, White, BJ, Gordon, LA, Fox, GA, Wadsworth, ME, Doyle, PH, Williams, BA, Fox, EJ, Shantaraman, A, Ryten, M, Goodwin, S, Ghiban, E, Wappel, R, Mavruk-Eskipehlivan, S, Miller, JB, Seyfried, NT, Nelson, PT, Fryer, JD & Ebbert, MTW 2025, 'Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq', Nature Biotechnology, vol. 43, no. 4, 177, pp. 635-646. https://doi.org/10.1038/s41587-024-02245-9

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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Statistical ‘Omics Research Collaborative (S'ORCe)

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

S'ORCe Collaborative Group (RENEWED)

Statistical ‘Omics Research Collaborative (S'ORCe)

Cite this