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TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes

GSE277844 Homo sapiens (human) RNA-seq (gene expression) 32 samples Submitted 2025/03/06 Platform GPL18573
At a glance

RNA-seq (gene expression) · human · 32 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Samples
32 samples: 12 conditions, mostly in triplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genesBrain : a journal of neurology · 2025
Summary (written by the submitters)
Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD) caused by mutations in TSC1 or TSC2 genes. TSC1 and TSC2 form a complex inhibiting mechanistic target of rapamycin complex-1 (mTORC1) signaling, leading to hyperactive mTORC1 signaling upon TSC1/2 loss of function.
Read the full summary ↓
Although rapalogs, which are FDA-approved allosteric mTORC1-selective inhibitors, are used to treat TSC-associated hamartomas, they are not effective for treating ND manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, whose activity is further modulated by the MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation in transcript-selective fashion depending on features in target mRNAs’ 5’ untranslated regions (5’UTRs), their effect on transcriptome-wide patterns of mRNA translation has not been compared. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we examined how loss of TSC2 affects gene expression via changes in mRNA abundance and translation at a transcriptome-wide scale. This revealed abundant mRNA translation alterations in TSC2-Null NPCs overlapping with those we previously observed in TSC1-Null NPCs. Surprisingly, numerous non-monogenic ASD- and NDD-associated genes, identified in patients harboring putative loss-of-function mutations, were selectively translationally suppressed in TSC2-Null NPCs consistent with their distinct repertoire of 5’UTR features. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study thereby establishes mTORC1-eIF4F and MNK-eIF4E-sensitive mRNA translation as key components in TSC, ASD and other neurodevelopmental disorders; and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.
Published in
TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes
Martin P, Szkop KJ, Robert F et al. · Brain : a journal of neurology 2025 · PMID 40037376 · doi:10.1093/brain/awaf081
This dataset
Open GSE277844 in finder → Find more human RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE277844_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1164315 and SRA study SRP534290. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40037376) ↗
Study design
12 conditions, mostly in triplicate
WT_DMSO_Poly ×3 WT_DMSO_Total ×3 WT_eFT508_Poly ×3 WT_eFT508_Total ×3 TSC2null_DMSO_Poly ×3 TSC2null_DMSO_Total ×3 TSC2null_eFT508_Poly ×3 TSC2null_eFT508_Total ×3 +4 more

Supports a between-group comparison across 32 samples.

How we read this: 12 replicated groups read from 32 sample titles; they account for 32 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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