ArticleCell systems2025
Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders.
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Article in Cell systems, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Intrinsic coordination of dynamic molecular signatures shape the human prefrontal cortex.bioRxiv : the preprint server for biology · 2026Article
- GPU-accelerated modeling of biological regulatory networks.Scientific reports · 2026Article
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Authors and funding
36 authors.
Yuan MeiDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA.
Maya L GosztylaDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA.
Xinzhu TanDepartment of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 1A1, Canada.
Lara E DozierDepartment of Neurobiology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Brent WilkinsonZilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.
Justin McKetneyGladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, Quantitative Biosciences Institute, San Francisco, CA 94158, USA; University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, CA 94143, USA.
John LeeDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Michael ChenDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Dorothy TsaiDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Hema KopalleDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA.
Marina A GritsenkoBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Nicolas HartelMork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
Nicholas A GrahamMork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
Ilse FloresMork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
Stephen K Gilmore-HallDepartment of Neurobiology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Shuhao XuDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA.
Charlotte A MarquezDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Sophie N LiuDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Dylan FongDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Jing ChenDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Kate LiconDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Derek HongDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Sarah N WrightDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Jason F KreisbergDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA.
Alexi NottDepartment of Brain Sciences, Imperial College London, White City Campus, London W12 7RH, UK; UK Dementia Research Institute, Imperial College London, White City Campus, London W12 0BZ, UK.
Richard D SmithBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Wei-Jun QianBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Danielle L SwaneyGladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, Quantitative Biosciences Institute, San Francisco, CA 94158, USA; University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, CA 94143, USA.
Lilia M IakouchevaDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Nevan J KroganGladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, Quantitative Biosciences Institute, San Francisco, CA 94158, USA; University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, CA 94143, USA.
Gentry N PatrickDepartment of Neurobiology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Yang ZhouDepartment of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 1A1, Canada.
Guoping FengMcGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Marcelo P CobaZilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: coba@usc.edu.
Gene W YeoDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA. Electronic address: geneyeo@ucsd.edu.
Trey IdekerDivision of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.
Funding
Equipment Supplement Request for a Research Resource for Ultra-sensitive High Throughput ProteomicsP41GM103493 · NIGMS · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI PAYNE, SAMUEL H · 2012 to 2022
$22.6MThe Psychiatric Cell Map Initiative: Connecting Genomics, Subcellular Networks, and Higher Order PhenotypesU01MH115747 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAMPMANN, MARTIN, KROGAN, NEVAN J · 2018 to 2022
$19.6MFunctional RNA elements in the human genomeR01HG004659 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Kevin Daniel Corbett, Eugene Wei-Ming Yeo · 2008 to 2026
$12.4MA Comprehensive Functional Map of Human Protein-RNA InteractionsU41HG009889 · NHGRI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI GRAVELEY, BRENTON R. · 2018 to 2021
$9.4MA comprehensive binding and functional map of human RNA-binding proteinsU24HG009889 · NHGRI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI GRAVELEY, BRENTON R., YEO, EUGENE WEI-MING · 2022 to 2025
$5.5MDissecting the role of thalamic inhibition in neurodevelopmental diseasesR01NS098505 · NINDS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI FENG, GUOPING, HALASSA, MICHAEL M · 2016 to 2020
$3.2MRegulation of postsynaptic protein interaction networks in complex brain disordersR01MH115005 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI COBA, MARCELO PABLO · 2018 to 2022
$2.9MIntegrative functional genomic study of pathways impacted by recurrent autism CNVR01MH108528 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI IAKOUCHEVA, LILIA M, MUOTRI, ALYSSON R. · 2016 to 2020
$2.6MRescue of Cul3 haploinsufficiency phenotypes with CRISPR-mediated Cul3 activationR21MH128827 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI IAKOUCHEVA, LILIA M · 2022 to 2023
$435kData-driven map of the postsynaptic density to decipher autism pathogenesisF32MH124408 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MEI, YUAN NA · 2020 to 2023
$222kNHGRI NIH HHS R01 HG004659NHGRI NIH HHS U24 HG009889NHGRI NIH HHS U41 HG009889NIGMS NIH HHS P41 GM103493NIMH NIH HHS F32 MH124408NIMH NIH HHS R01 MH108528NIMH NIH HHS R01 MH115005NIMH NIH HHS R21 MH128827NIMH NIH HHS U01 MH115747NINDS NIH HHS R01 NS098505
Abstract
The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data. This data-driven framework identifies proteins with key molecular features intrinsic to the synapse, including characteristic patterns of biophysical interactions and cross-tissue expression. The multi-omic analysis captures synaptic proteins across developmental stages and experimental systems, including 493 synaptic candidates supported by proteomics. We further investigate three such proteins that are associated with neurodevelopmental disorders-Cullin 3 (CUL3), DEAD-box helicase 3 X-linked (DDX3X), and Y-box binding protein-1 (YBX1)-by mapping their networks of physically interacting synapse proteins or transcripts. Our study demonstrates the potential of an integrated multi-omic approach to more comprehensively resolve the synaptic architecture.
Indexed as
Neurodevelopmental DisordersSynapsesUbiquitin-Protein LigasesBrainHumansInduced Pluripotent Stem CellsMultiomicsNeuronsProteomicsRNA Processing, Post-TranscriptionalTranscriptomeUbiquitin-Protein LigasesCUL3DDX3Xmachine learningmulti-omicsproteomicssynapseYBX1
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