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KDM3A and KDM3B regulate alternative splicing in mouse pluripotent stem cells
Caleb M Dillingham1,2,3, Harshini Cormaty1,2,4, Ellen C Morgan1,2
1Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Iscience
|June 13, 2025
Summary
Histone demethylases KDM3A and KDM3B regulate mouse stem cell identity through RNA splicing, not just histone modification. This reveals a new role in post-transcriptional gene regulation.
Area of Science:
- Cell Biology
- Epigenetics
- Molecular Biology
Background:
- Histone modifying enzymes maintain cell identity by regulating chromatin.
- Mouse embryonic stem cells (mESCs) have low gene repression for rapid differentiation.
- KDM3 family demethylases remove repressive H3K9me2 marks.
Purpose of the Study:
- To investigate the role of KDM3 proteins in mouse pluripotent embryonic stem cells (mESCs).
- To explore potential non-histone modification functions of KDM3A and KDM3B.
- To understand the impact of KDM3 proteins on RNA processing and cell identity.
Main Methods:
- Proteomic analysis to identify KDM3 interacting partners.
- Acute degradation of endogenous KDM3A and KDM3B proteins.
- Analysis of splicing patterns and histone modification status (H3K9me2).
Main Results:
- KDM3A and KDM3B interact with RNA processing factors (EFTUD2, PRMT5).
- Protein degradation alters splicing independently of H3K9me2 or catalytic activity.
- Splicing changes mimic ground state pluripotency and affect key genes (Dnmt3b, Tcf12).
Conclusions:
- KDM3 proteins have a non-canonical role in post-transcriptional regulation.
- Histone demethylases can influence cell identity through alternative splicing.
- These findings expand the known functions of KDM3 family enzymes.
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