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Development of a potent epigenetic editor targeting human PCSK9 with durable reduction of cholesterol in mice and non-human primates [hybrid capture methylseq]

GSE282436 Homo sapiens (human) ChIP-seq / ATAC-seq (genome binding and open chromatin) 66 samples Submitted 2025/02/05 Platform GPL16417Platform GPL15520
At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 66 samples

What it is
ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
Organism
Homo sapiens (human)
Samples
66 samples: 16 conditions, mostly with about 4 replicates eachGroups 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
A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levelsNature medicine · 2025
Summary (written by the submitters)
DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor.
Read the full summary ↓
A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo
Published in
A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels
Tremblay F, Xiong Q, Shah SS et al. · Nature medicine 2025 · PMID 39930141 · doi:10.1038/s41591-025-03508-x
This dataset
Open GSE282436 in finder → Find more ChIP / ATAC / CUT&Tag 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 GSE282436_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: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.

Also filed as BioProject PRJNA1188579 and SRA study SRP546520. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39930141) ↗
Study design
16 conditions, mostly with about 4 replicates each
hPCSK9 tg mouse liver, PCSK9-EE, day365, ×6 hPCSK9 tg mouse liver, PCSK9-EE, ×5 hPCSK9 tg mouse liver, dCas9-TET, ×5 hPCSK9 tg mouse liver, Vehicle, day28, ×4 hPCSK9 tg mouse liver, WTCas9, day28, ×4 hPCSK9 tg mouse liver, CRISPRi, day28, ×4 hPCSK9 tg mouse liver, PCSK9-EE, day28, ×4 hPCSK9 tg mouse liver, Cas9, Resected, ×4 +9 more

Supports a between-group comparison across 65 samples.

How we read this: 16 replicated groups read from 66 sample titles; they account for 65 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

+ 26 more — browse all 66 samples with per-sample file links →

Datasets on a similar topic

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