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Dual DNA demethylation mechanisms implement epigenetic memory driven by the pioneer factor PAX7
Juliette Harris1, Alexandre Mayran1, Arthur Gouhier1
1Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal, Montréal H2W1R7, Canada.
Science Advances
|May 16, 2025
Summary
Pioneer transcription factor PAX7 initiates new cell fates by triggering DNA demethylation. PAX7 interacts with UHRF1 to block DNMT1 activity, aiding epigenetic memory establishment.
Area of Science:
- Epigenetics
- Molecular Biology
- Developmental Biology
Background:
- Pioneer transcription factors establish new cell fates by opening chromatin.
- These factors also create epigenetic memory via DNA demethylation, but mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanism by which pioneer factor PAX7 (paired box 7) induces DNA demethylation.
- To investigate the role of PAX7 in establishing epigenetic memory at enhancers.
Main Methods:
- Investigated PAX7 interaction with UHRF1 (E3 ubiquitin-protein ligase) and DNMT1 (DNA methyltransferase 1).
- Assessed the impact of PAX7 on UHRF1-DNMT1 complex activity.
- Examined the contribution of TET (ten-eleven translocation) DNA demethylases.
Main Results:
- PAX7 directly interacts with UHRF1, preventing its association with DNMT1.
- PAX7 binding inhibits DNMT1's DNA methylation maintenance activity post-replication.
- TET demethylases assist in replication-dependent DNA methylation loss.
Conclusions:
- PAX7 hijacks the UHRF1-DNMT1 complex to block DNA methylation maintenance after replication.
- This mechanism, aided by TET demethylases, leads to DNA methylation dilution and epigenetic memory.
- PAX7 plays a crucial role in regulating DNA methylation dynamics during cell fate determination.
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