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Single-cell and isoform-specific translational profiling of the mouse brain with long-read sequencing [scRNA-Seq, longread]

ABSTRACT: The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation. Among these, alternative splicing has been shown to drive cell type specificity and, when disrupted, is strongly linked to neurological disorders. However, genome-wide measurements of mRNA translation with isoform-sensitivity at single-cell (sc) resolution have not been achieved. To address this, we deployed Ribo-STAMP (Surveying Ribosomal Targets by APOBEC-Mediated Profiling) coupled with long-read scRNA-sequencing (scRNA-seq) in the brain. We generated the first isoform-sensitive sc 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 eight different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. Surprisingly, we found that CA3 exhibited higher basal translation compared to CA1, as confirmed by metabolic labeling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell type- and isoform-specific translation drives brain physiology and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE314059 | GEO | 2025/12/22

REPOSITORIES: GEO

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Single-cell and isoform-specific translational profiling of the mouse brain [scRNA-seq]

Project description:The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation. Among these, alternative splicing has been shown to drive cell type specificity and, when disrupted, is strongly linked to neurological disorders. However, genome-wide measurements of mRNA translation with isoform-sensitivity at single-cell (sc) resolution have not been achieved. To address this, we deployed Ribo-STAMP (Surveying Ribosomal Targets by APOBEC-Mediated Profiling) coupled with short- and long-read scRNA-sequencing (scRNA-seq) in the brain20. We generated the first isoform-sensitive sc 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 eight different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. Surprisingly, we found that CA3 exhibited higher basal translation compared to CA1, as confirmed by metabolic labeling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell type- and isoform-specific translation drives brain physiology and disease.

2025-12-22 | GSE314058 | GEO

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

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Single cell and isoform-specific translational profiling of the mouse brain [Bulk RNA-seq]

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Single cell and isoform-specific translational profiling of the mouse brain [Ribo-STAMP]

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mRNA-Seq of mouse Mettl3 cKO and Fto cKO hippocampus after fear conditioning

Project description:N6-Methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo are currently unknown. Here, we investigated the effect of gene deletion of Mettl3, a m6A methyltransferase, and Fto, a m6A and m6Am demethlyase, induced in adulthood in excitatory neurons of the CA1 and CA3 in the hippocampus (Nex-CreERT2 Mettl3 or Fto cKO) on the transcriptome of CA1 and CA3 as well as the transcriptomic response of the CA1 and CA3 transcriptome to fear conditioning.

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2016-07-07 | PXD004078 | Pride

Polysomal and total RNA in controls and after 10 min global brain ischemia and 8 hours of reperfusion

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Subregion-specific proteomic signature in the hippocampus for memory formation in adult mice

Project description:The hippocampal formation is a brain structure essential for higher-order cognitive functions. It has exquisite differences in anatomical organization and cellular composition, and hippocampal sub-regions have different properties and functional roles. Areas CA1 and CA3 in particular, are key sub-regions for learning and memory formation that fulfill complementary but specific functions. The molecular basis for such specific properties and the link to learning and memory remain unknown. Here using a SWATH-MS proteomic approach and bioinformatic tools, we identify a selective proteomic signature in area CA1 and CA3, and reveal their specific dynamics during memory formation. We show that 30% of all quantifiable proteins are differentially expressed in area CA1 and CA3 at baseline, and that each proteome responds differently during the formation of memory for object or object location. Using clustering and cross-correlational analyses, we outline specific temporal proteomic profiles and an increased correlation between both forms of memory within area CA1, but not within area CA3. These results provide new insight into a proteomic basis for hippocampal sub-region molecular and functional specificity.

2018-03-28 | PXD006382 | Pride

Epigenetic Transgenerational Alterations to Stress Response in Brain Gene Networks and Behaviour

Project description:Ancestral environmental exposures that promote epigenetic transgenerational inheritance influence all aspects of an individual’s life history. Stress experienced during adolescence can affect adult physiological and behavioural phenotypes. The current study utilized a systems biology approach to investigate the interactions of these two forms of epigenetic modification, one carried in the germline transgenerationally and the other contained in the context of life history. A transgenerational epigenetic imprint left by the fungicide vinclozolin promoted regional specific brain gene networks that influenced chronic restraint stress responses to alter adult physiological, brain and behavioural phenotypes. The environmentally-induced epigenetic transgenerational inheritance was found to interact with early life stress response to impact the adult brain genome activity to bring “the phenotype into being”. We used microarrays to determine genes expressed differentially in rats' 4 brain areas - basolateral amygdala (BLA), primary and secondary motor cortex (Crtx), CA1 of the hippocampus (CA1), and CA3 of the hippocampus (CA3) - due to Vinclozolin treatments of their grand-grandmothers and/or to stress in adolescence age. For each of 4 brain areas (BLA, CRTX, CA1, and CA3), RNA samples from 4 treatment groups - stressed control (St-Con), non-stressed control (NSt-Con), stressed vinclozolin (St-Vin), and non-stressed vinclozolin (NSt-Vin) - were compared to each other. Each treatment groups contained 3 biological replica. RNA for each replica was pooled from 4 individual animals forming a certain dyad group.

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