Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation

Sugata Manna, Jong Kyong Kim, Catherine Baugé, Margaret Cam, Yongmei Zhao, Jyoti Shetty, Melanie S. Vacchio, Ehydel Castro, Bao Tran, Lino Tessarollo and Rémy Bosselut ()
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Sugata Manna: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Jong Kyong Kim: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Catherine Baugé: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Margaret Cam: Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Yongmei Zhao: Leidos Biomedical Research, Frederick National Laboratory for Cancer Research
Jyoti Shetty: Leidos Biomedical Research, Frederick National Laboratory for Cancer Research
Melanie S. Vacchio: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Ehydel Castro: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Bao Tran: Leidos Biomedical Research, Frederick National Laboratory for Cancer Research
Lino Tessarollo: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Rémy Bosselut: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Although histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive. To investigate this, we conditionally inactivated the two H3K27Me3 demethylases, Jmjd3 and Utx, in non-dividing intrathymic CD4+ T-cell precursors. Here we show that both enzymes redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Thymocyte expression of S1pr1 was not rescued in Jmjd3- and Utx-deficient male mice, which carry the catalytically inactive Utx homolog Uty, supporting the conclusion that it requires H3K27Me3 demethylase activity. These findings demonstrate that Jmjd3 and Utx are required for T-cell development, and point to a requirement for their H3K27Me3 demethylase activity in cell differentiation.

Date: 2015
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DOI: 10.1038/ncomms9152

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