GEO series

Dysregulated TGFb-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis

GSE315927 Homo sapiens (human) Single-cell RNA-seq 12 samples Submitted 2026/03/06 Platform GPL34281

At a glance

Single-cell RNA-seq · human · 12 samples

What it is: Single-cell RNA-seqGene activity measured in thousands of individual cells, so cell types can be told apart. Read from the summary: GEO's own type field only says 'expression profiling by sequencing', so confirm it in the paper.
Organism: Homo sapiens (human)
Samples: 12 samples: 12 samples, each with a distinct title — no replicated groupsGroups 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: Dysregulated TGFβ-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve StenosisbioRxiv : the preprint server for biology · 2026

Summary (written by the submitters)

Pulmonary valve stenosis (PVS) is the most common congenital heart defect in Noonan syndrome (NS) and related RASopathies, yet the molecular mechanisms that link the underlying pathogenic variants to the valve pathology remains poorly defined. Here, we utilized a human iPSC-based valve differentiation platform to generate the cardiac valve cell lineage—including fibrosa and spongiosa valve interstitial cell (VIC) subtypes.

Read the full summary ↓

Applying this model to CRISPR-edited iPSCs carrying NS- and Noonan syndrome with multiple lentigines (NSML)-associated variants, we identified early mesodermal and endocardial specification defects in all lines. Additionally, we found that NS-iPSCs exhibited fibrosa VIC-specific defects in endothelial-to-mesenchymal transition (EndMT), which was most pronounced in PTPN11N308D (N308D) cells. Through single-cell transcriptomics, we revealed widespread dysregulation of extracellular matrix (ECM) programs in N308D fibrosa VICs, including increased expression of collagens and proteoglycans, as well as dysregulation of multiple genes involved in ECM remodeling. We also detected activation of RAS-MAPK, TGFb, and fibrosis-associated pathways in our transcriptional dataset. We then characterized the global signaling changes in N308D fibrosa VICs through mass spectrometry-based phosphoproteomic profiling, which identified coordinated increases in ERK, PKC, and stress-related kinases, as well as enhanced activity at the TGFb receptor. Functionally, we observed that N308D fibrosa VICs had an exaggerated upregulation of ECM genes in the presence of TGFb2 ligand, suggesting that these cells are hypersensitive to TGFb stimulation. Furthermore, we demonstrated that this pathological ECM-program occurs independently of BAMBI, a negative regulator of TGFb signaling that was found to be decreased in N308D fibrosa VICs. Lastly, we performed histopathological analyses of stenotic pulmonary valves from two NS infants, which demonstrated marked overproduction and disorganization of ECM, mirroring the findings from our iPSC-based disease model. Together, our data reveals a central mechanism where NS-associated alleles sensitize fibrosa VICs to TGFb, which leads to aberrant downstream TGFb signaling and drives the pathological ECM program in NS-associated PVS.

Published in

Dysregulated TGFβ-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis

Liu CZ, Patel S, Sidoli S et al. · bioRxiv : the preprint server for biology 2026 · PMID 41648231 · doi:10.64898/2026.01.16.700032

This dataset

Open GSE315927 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 GSE315927_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: Single-cell studies usually ship their counts as 10x files (matrix.mtx, barcodes.tsv, features.tsv), an .h5 file, or an .rds / .h5ad object that Seurat or Scanpy can open. Look for those among the supplementary files.

Also filed as BioProject PRJNA1399970 and SRA study SRP660674. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41648231) ↗

Study design

12 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 12 sample titles: 12 distinct titles with little repetition. 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

GSM9440157 WT (unedited control), Day 14 Endocardial
GSM9440158 WT (unedited control), Day 26 Fibrosa VICs
GSM9440159 WT (unedited control), Day 26 Spongiosa VICs
GSM9440160 RAF1 S257L, Day 14 Endocardial
GSM9440161 RAF1 S257L, Day 26 Fibrosa VICs
GSM9440162 RAF1 S257L, Day 26 Spongiosa VICs
GSM9440163 PTPN11 N308D, Day 14 Endocardial
GSM9440164 PTPN11 N308D, Day 26 Fibrosa VICs
GSM9440165 PTPN11 N308D, Day 26 Spongiosa VICs
GSM9440166 PTPN11 Y279C, Day 14 Endocardial
GSM9440167 PTPN11 Y279C, Day 26 Fibrosa VICs
GSM9440168 PTPN11 Y279C, Day 26 Spongiosa VICs

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