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Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression

GSE337675 Homo sapiens (human) RNA-seq (gene expression) 28 samples Submitted 2026/07/14 Platform GPL24676Platform GPL34281
At a glance

RNA-seq (gene expression) · human · 28 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
28 samples: 10 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.
Summary (written by the submitters)
Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined.
Read the full summary ↓
Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Stable isotope tracing revealed preservation of glucose-derived carbon incorporation into tricarboxylic acid (TCA) cycle intermediates, suggesting compensatory metabolic adaptation to maintain pyruvate-dependent TCA cycle metabolism. Overexpression of truncating ASXL1 constructs in cell models replicated this phenotype. Mechanistically, truncated ASXL1 shows decreased occupancy at an H3K4me3-marked enhancer upstream of mitochondrial pyruvate carrier 2 (MPC2), together with BAP1 co-recruitment, and selectively reduces MPC1 and MPC2 protein levels through a mechanism that is independent of transcript levels. Pharmacologic inhibition of the MPC reproduces both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation also increases glycolytic flux but without reducing the MPC abundance, implicating that reduced MPC abundance acts upstream of signaling dysregulation. These findings define a previously unrecognized pathway connecting gain-of-function ASXL1 truncation to chromatin-level regulation of mitochondrial pyruvate transport, and identify the MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutated myeloid malignancies.
This dataset
Open GSE337675 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 GSE337675_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 PRJNA1490572 and SRA study SRP715560. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗
Study design
10 conditions, mostly in triplicate
HEK293T, ASXL1 Transfection 1-1304, ×3 HEK293T, ASXL1 Transfection 1-1541, ×3 HEK293T, ASXL1 Transfection 1-479, ×3 HEK293T, Control Transfection STOP, ×3 Caco-2, ASXL1 Transfection 1-1304, ×3 Caco-2, ASXL1 Transfection 1-479, ×3 Caco-2, Control GFP, ×3 Caco-2, Control, ×3 +2 more

Supports a between-group comparison across 28 samples.

How we read this: 10 replicated groups read from 28 sample titles; they account for 28 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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