Journal
EMBO JOURNAL
Volume 35, Issue 14, Pages 1550-1564Publisher
WILEY
DOI: 10.15252/embj.201593317
Keywords
development; epigenetics; histone demethylation; Kdm4; transcription
Categories
Funding
- Netherlands Organization for Scientific Research (NWO) [825.10.027]
- EMBO [1204-2014]
- Danish Cancer Society
- Danish National Research Foundation [DNRF 82]
- Lundbeck Foundation
- Novo Nordisk Foundation [The Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease] [NNF14CC001]
- Novo Nordisk Foundation [The Novo Nordisk Foundation Center for Protein Research] [NNF14CC001]
- Novo Nordisk Foundation Center for Protein Research [PI Jakob Nilsson] Funding Source: researchfish
- Novo Nordisk Foundation Section for Basic Stem Cell Biology [Helin group NNF] Funding Source: researchfish
- The Danish Cancer Society [R90-A5943] Funding Source: researchfish
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Chromatin-associated proteins are essential for the specification and maintenance of cell identity. They exert these functions through modulating and maintaining transcriptional patterns. To elucidate the functions of the Jmjd2 family of H3K9/H3K36 histone demethylases, we generated conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). We report that while individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. We further show that Jmjd2a and Jmjd2c both localize to H3K4me3-positive promoters, where they have widespread and redundant roles in preventing accumulation of H3K9me3 and H3K36me3. Jmjd2 catalytic activity is required for ESC maintenance, and increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity.
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