GEO series

Investigating the mechanisms by which SMAD6 mutations cause tracheoesophageal birth defects

GSE305960 Homo sapiens (human) RNA-seq (gene expression) 54 samples Submitted 2025/12/31 Platform GPL24676

At a glance

RNA-seq (gene expression) · human · 54 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: 54 samples
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.

Summary (written by the submitters)

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) are tracheoesophageal (TE) birth defects which affect 1 in 3000 live births in the United States. EA occurs when the esophagus fails to form a continuous tube from the oral cavity to the stomach and TEF occurs when there is an abnormal connection between the trachea and esophagus.

Read the full summary ↓

The etiology of EA/TEF arises when the common foregut tube fails to properly separate into the esophagus and respiratory tract during early embryogenesis. This process is essential for proper organ function and involves complex molecular and morphological processes. As part of a multi-institutional project aiming to identify genes causing tracheoesophageal defects, we identified two EA/TEF patients who presented with different mutations in SMAD6, a BMP signaling inhibitor. We used a CRISPR-based approach to knock down smad6 in frog embryos and observed separation defects of the esophagus and trachea, supporting the conclusion that SMAD6 mutations in humans may cause EA/TEF. To investigate the role of SMAD6 during human development, we used CRISPR to generate human pluripotent stem cell lines with loss-of-function alleles in SMAD6. The human foregut is comprised of an inner layer of endoderm-derived epithelium surrounded by mesenchyme, and it is not known if SMAD6 functions in either or both layers. To elucidate this, we investigated the role of SMAD6 in either foregut epithelium or mesenchyme, or both in combination. Our analysis of human SMAD6-/- tracheoesophageal epithelium and mesenchyme reveals an increase in BMP/TGFβ signaling, consistent with its role as a repressor of these pathways. We also observed patterning defects in both tissue types; SMAD6 mutant endoderm shows increased expression of distal gut tube markers and SMAD6 mutant mesenchyme shows increased expression of cardiac markers. Furthermore, we observed cell differentiation changes, where SMAD6-/- mesenchyme had decreased ability to form CD31-positive vasculature, as well as changes in genes involved in processes such as cell migration and extracellular matrix deposition, which are critical for mesenchyme morphogenesis and differentiation during the process of TE separation. Our results suggest SMAD6 mutations impact the identity and function of human engineered TE tissue. By identifying pathways significant for TE development during early embryogenesis, our results contribute to understanding how patient mutations cause congenital malformations.

This dataset

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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 GSE305960_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 PRJNA1308530 and SRA study SRP610352. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Samples in this study

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+ 54 more — browse all 54 samples with per-sample file links →

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