The ZBTB24-CDCA7-HELLS Axis Suppresses the Totipotent 2C-Like Reprogramming by Maintaining Dux Methylation and Repression

Authors

Dan Guo
Zeling Du
Youqi Liu
Meiqi Lin
Yue Lu
Swanand Hardikar
Yanna Xue
Jinghong Zhang
Taiping Chen
Jiameng Dan

Publication Date

4-10-2025

Journal

Nucleic Acids Research

DOI

10.1093/nar/gkaf302

PMID

40226918

PMCID

PMC11995263

PubMedCentral® Posted Date

4-14-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Two-cell-like cells (2CLCs), a rare population (∼0.5%) in mouse embryonic stem cell (mESC) cultures, are in a transient totipotent-like state resembling that of 2C-stage embryos, and their discovery and characterization have greatly facilitated the study of early developmental events, such as zygotic genome activation. However, the molecular determinants governing 2C-like reprogramming remain to be elucidated. Here, we show that ZBTB24, CDCA7, and HELLS, components of a molecular pathway that is involved in the pathogenesis of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, function as negative regulators of 2C-like reprogramming by maintaining DNA methylation of the Dux cluster, a master inducer of the 2C-like state. Disruption of the ZBTB24-CDCA7-HELLS axis results in Dux hypomethylation and derepression, leading to dramatic upregulation of 2C-specific genes, which can be reversed by site-specific re-methylation in the Dux promoter. We also provide evidence that CDCA7 is enriched at the Dux cluster and recruits the CDCA7-HELLS chromatin remodeling complex to constitutive heterochromatin. Our study uncovers a key role for the ZBTB24-CDCA7-HELLS axis in safeguarding the mESC state by suppressing the 2C-like reprogramming.

Keywords

Animals, Mice, Cellular Reprogramming, Homeodomain Proteins, DNA Methylation, DNA Helicases, Mouse Embryonic Stem Cells, Promoter Regions, Genetic, Nuclear Proteins, Repressor Proteins

Published Open-Access

yes

Recommended Citation

Guo, Dan; Du, Zeling; Liu, Youqi; et al., "The ZBTB24-CDCA7-HELLS Axis Suppresses the Totipotent 2C-Like Reprogramming by Maintaining Dux Methylation and Repression" (2025). Faculty, Staff and Student Publications. 4291.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4291