Single-cell and isoform-specific translational profiling of the mouse brain

The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation<sup>1-11</sup>. Among these, alternative splicing has been shown to drive cell-type specificity and, when disrupted, is strongly linked to neurological disorders<sup>12-17</sup>. However, genome-wide measurements of mRNA translation with isoform sensitivity at single-cell resolution have not been achieved. To address this, we deployed Surveying Ribosomal Targets by APOBEC-Mediated Profiling (Ribo-STAMP) coupled with short-read and long-read single-cell RNA sequencing in the brain<sup>18</sup>. We generated the first isoform-sensitive single-cell translatomes of the mouse hippocampus at postnatal day 25, discovering cell-type-specific translation of 3,857 alternative transcripts across 1,641 genes and identifying isoforms of the same genes undergoing differential translation within and across 8 different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. We found that CA3 exhibited higher basal translation compared with CA1, as confirmed by metabolic labelling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell-type-specific and isoform-specific translation drives brain physiology and disease.

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Publication Details

Journal
Nature
Published
2026-02-18
DOI
https://doi.org/10.1038/s41586-026-10118-1
Primary Topic
Single-cell and spatial transcriptomics
Type
article
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article

Single-cell and isoform-specific translational profiling of the mouse brain

Zhengyuan Pang, Akanksha Khorgade, Grady G. Nguyen, Federico Zampa et al.
Nature
Single-cell and spatial transcriptomics
article

Single-cell and isoform-specific translational profiling of the mouse brain

Zhengyuan Pang, Akanksha Khorgade, Grady G. Nguyen, Federico Zampa, Steven M. Blue, Kristopher W. Brannan, Wenhao Jin, Cailynn C. Wang, Giordano Lippi, David Sievert, Chun-Yuan Chen, Eric Kofman, Samantha L. Sison, Pratibha Jagannatha, Orel Mizrahi, Sourish Mukhopadhyay, Jack T. Naritomi, Su Yeun Choi, LI YE, Asa Shin, Gene W. Yeo, Aziz M. Al’Khafaji, Dong Yang
article en

Abstract

The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation<sup>1-11</sup>. Among these, alternative splicing has been shown to drive cell-type specificity and, when disrupted, is strongly linked to neurological disorders<sup>12-17</sup>. However, genome-wide measurements of mRNA translation with isoform sensitivity at single-cell resolution have not been achieved. To address this, we deployed Surveying Ribosomal Targets by APOBEC-Mediated Profiling (Ribo-STAMP) coupled with short-read and long-read single-cell RNA sequencing in the brain<sup>18</sup>. We generated the first isoform-sensitive single-cell translatomes of the mouse hippocampus at postnatal day 25, discovering cell-type-specific translation of 3,857 alternative transcripts across 1,641 genes and identifying isoforms of the same genes undergoing differential translation within and across 8 different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. We found that CA3 exhibited higher basal translation compared with CA1, as confirmed by metabolic labelling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell-type-specific and isoform-specific translation drives brain physiology and disease.

Nature
Broad Institute (US), Scripps Research Institute (US), Houston Methodist (US), Scripps Health (US), Harvard University (US), Scripps Institution of Oceanography (US), University of California San Diego (US), Scripps (United States) (US), Innovative Research (United States) (US)
Openalex Percentile: Top 51%
Single-cell and spatial transcriptomics
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