Abstract
Genetic studies have shown that aberrant activation of p53 signaling leads to embryonic lethality. Maintenance of a fine balance of the p53 protein level is critical for normal development. Previously, we have reported that Jmjd5, a member of the Jumonji C (JmjC) family, regulates embryonic cell proliferation through the control of Cdkn1a expression. Since Cdkn1a is the representative p53-regulated gene, we have examined whether the expression of other p53 target genes is coincidentally upregulated with Cdkn1a in Jmjd5-deficient embryos. The expression of a subset of p53-regulated genes was increased in both Jmjd5 hypomorphic mouse embryonic fibroblasts (MEFs) and Jmjd5-deficient embryos at embryonic day 8.25 without the induced expression of Trp53. Intercrossing of Jmjd5-deficient mice with Trp53 knockout mice showed that the growth defect of Jmjd5 mutant cells was significantly recovered under a Trp53 null genetic background. Chromatin immunoprecipitation analysis in Jmjd5 hypomorphic MEFs indicated the increased recruitment of p53 at several p53 target gene loci, such as Cdkn1a, Pmaip1, and Mdm2. These results suggest that Jmjd5 is involved in the transcriptional regulation of a subset of p53-regulated genes, possibly through the control of p53 recruitment at the gene loci. In Jmjd5-deficient embryos, the enhanced recruitment of p53 might result in the abnormal activation of p53 signaling leading to embryonic lethality.
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Acknowledgments
We thank Dr A. Hirao (Kanazawa University, Japan) for providing Cdkn1a- and Trp53-deficient mice, Dr. T. Nakamura (Kansai Medical University, Japan) for providing the pEF6/FLAG-His6 plasmid, Dr. M. Yoshida (Japanese Foundation for Cancer Research, Japan) for providing the HA-p53-expression vector, and Dr. H. Kimura (Tokyo Institute of Technology, Japan) for providing the anti-H3K36me2 antibody.
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This work was supported by Grants-in-Aid for Scientific Research C (Research Project numbers: 25460266 to A.I. and 15 K08263 to T.S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Fig. S1
Immunofluorescence with anti-single-strand DNA antibody to visualize apoptotic cells (red) in (a, b) wild-type and (c, d) Jmjd5Δ/Δ embryos at E8.5. DAPI (blue) was used for nuclear staining. Bars 100 μm (GIF 213 kb)
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Ishimura, A., Terashima, M., Tange, S. et al. Jmjd5 functions as a regulator of p53 signaling during mouse embryogenesis. Cell Tissue Res 363, 723–733 (2016). https://doi.org/10.1007/s00441-015-2276-7
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DOI: https://doi.org/10.1007/s00441-015-2276-7