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Single-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue
Open accessAbstract
Single-nuclei RNA sequencing characterizes cell types at the gene level. However, compared to single-cell approaches, many single-nuclei cDNAs are purely intronic, lack barcodes and hinder the study of isoforms. Here we present single-nuclei isoform RNA sequencing (SnISOr-Seq). Using microfluidics, PCR-based artifact removal, target enrichment and long-read sequencing, SnISOr-Seq increased barcoded, exon-spanning long reads 7.5-fold compared to naive long-read single-nuclei sequencing. We applied SnISOr-Seq to adult human frontal cortex and found that exons associated with autism exhibit coordinated and highly cell-type-specific inclusion. We found two distinct combination patterns: those distinguishing neural cell types, enriched in TSS-exon, exon-polyadenylation-site and non-adjacent exon pairs, and those with multiple configurations within one cell type, enriched in adjacent exon pairs. Finally, we observed that human-specific exons are almost as tightly coordinated as conserved exons, implying that coordination can be rapidly established during evolution. SnISOr-Seq enables cell-type-specific long-read isoform analysis in human brain and in any frozen or hard-to-dissociate sample.
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“Emerging long-read sequencing approaches enable us to profile cellular transcriptomes at isoform resolution,8,31,32,33 thus providing new opportunities to model the relationships between isoforms using co-expression network analysis.”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [33]
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hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data
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Metadata
- Authors
- Hardwick, S. A., Hu, W., Joglekar, A., Fan, L., Collier, P. G., Foord, C., Balacco, J., Lanjewar, S., Sampson, M. M., Koopmans, F., Prjibelski, A. D., Mikheenko, A., Belchikov, N., Jarroux, J., Lucas, A. B., Palkovits, M., Luo, W., Milner, T. A., Ndhlovu, L. C., Smit, A. B., Trojanowski, J. Q., Lee, V. M. Y., Fedrigo, O., Sloan, S. A., Tombácz, D., Ross, M. E., Jarvis, E., Boldogkői, Z., Gan, L., & Tilgner, H. U.
- Affiliations
- Weill Cornell Medicine (US)
- Rockefeller University (US)
- Emory University (US)
- Amsterdam Neuroscience (NL)
- St Petersburg University (RU)
- Agilent Technologies (United States) (US)
- Semmelweis University (HU)
- University of Pennsylvania (US)
- University of Szeged (HU)
- Corresponding author
- Tilgner, Hagen U.
- ORCID
- Hardwick, Simon A.
- Hu, Wen
- Joglekar, Anoushka
- Fan, Li
- Foord, Careen
- Balacco, Jennifer
- Lanjewar, Samantha
- Sampson, Maureen McGuirk
- Koopmans, Frank
- Prjibelski, Andrey D.
- Mikheenko, Alla
- Belchikov, Natan
- Jarroux, Julien
- Palkovits, Miklós
- Luo, Wenjie
- Milner, Teresa A.
- Ndhlovu, Lishomwa C.
- Smit, August B.
- Trojanowski, John Q.
- Lee, Virginia M. Y.
- Fedrigo, Olivier
- Sloan, Steven A.
- Tombácz, Dóra
- Ross, M. Elizabeth
- Jarvis, Erich
- Boldogkői, Zsolt
- Gan, Li
- Tilgner, Hagen U.
- Venue
- Nature Biotechnology
- Published
- 2022-03-07
- Volume
- 40
- Issue
- 7
- Pages
- 1082-1092
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC9287170
- OpenAlex
- W4220958064
- Cited by
- 119
- References
- 59
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 32 · 2023: 26 · 2022: 11
- FWCI
- 8.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Biotechnology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Department of Health | National Health and Medical Research Council (APP1156531)
- Saint Petersburg State University (PURE 73023672)
- Semmelweis Egyetem (2017-1.2.1-NKP-2017-00002)
- Hungarian Brain Research Program, The Human Brain Tissue Bank, Semmelweis University
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (DA08259, U01 DA53625, U01 DA053625-01)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL136520)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (UM1AI164599)
- U.S. Department of Health & Human Services | National Institutes of Health (U19 AG062418, R01AG051390, U54NS100717, R01AG054214)
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH125956, 1RF1MH121267-01)
- Brain and Behavior Research Foundation (28172)
- Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal (FK128252, K128247)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (1R01NS105477, U54NS11717)
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD067244)
- Feil Family Foundation
- JPB Foundation
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (1R01GM135247-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- alternative splicing, barcoding, frozen brain tissue, human frontal cortex, autism spectrum disorder, long-read sequencing, microfluidics, target enrichment
- MeSH terms
- Brain, Exons, Humans, RNA, Alternative Splicing, Sequence Analysis, RNA, Protein Isoforms
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