# Methylome profiling of SetDB1-deficient ESCs reveals coordinated epigenetic cross-talk during pluripotency

Article · Bovee NGP, Habibi E, Liu Z, Hoogland SHA, Frölich S, Diepenbroek D, Bosman KCM, Arand J, Maksakova IA, Kranenbarg AK, Walter J, Brinkman AB, Mulder KW, Jansen JH, Vermeulen M, Lorincz M, Stunnenberg HG, Marks H

- Archive id: doi:10.1016/j.stemcr.2026.103075
- Published: 2026-09-03
- Venue: Stem cell reports
- DOI: https://doi.org/10.1016/j.stemcr.2026.103075
- PMID: 42692011
- PMCID: PMC13681314
- Citations: 0
- Source URL: https://doi.org/10.1016/j.stemcr.2026.103075
- PDF: https://europepmc.org/articles/PMC13681314/pdf
- Provenance: europepmc

## Abstract

SetDB1 is best known for catalyzing H3K9me3, but it also influences H3K27me3 deposition, CTCF-binding, and DNA methylation (DNAme). Given the interplay between DNAme and the other epigenetic features, we profiled DNAme following Setdb1 knockout (KO) in ground-state and serum-grown mouse embryonic stem cells (ESCs) to illuminate DNAme-dependent and -independent functions of SetDB1. Time-course whole-genome bisulfite sequencing of serum-grown ESCs shows that nearly half of SetDB1 binding sites are enriched with DNAme and H3K9me3, primarily at retrotransposons. Upon Setdb1 KO, both H3K9me3 and DNAme are reduced, with DNAme rapidly removed at many sites by TET enzymes. Some retrotransposons, primarily IAPs, are TET-resistant and lose DNAme slowly via passive dilution. Notably, SetDB1-mediated regulation of H3K27me3, CTCF-binding, and SMAD3 are uncoupled from the DNAme-H3K9me3 axis, and from each other. AlphaFold modeling and co-immunoprecipitation mass spectrometry suggest this uncoupling involves competitive binding to distinct SetDB1 protein domains, highlighting the complex coordination underlying SetDB1 functions.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [AI Protein Design & Structure Prediction](https://space-kitty.com/topics/protein-design)

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