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

• Published in: Nature communications Vol. 6; no. 1; p. 8152
• Main Authors: Manna, Sugata, Kim, Jong Kyong, Baugé, Catherine, Cam, Margaret, Zhao, Yongmei, Shetty, Jyoti, Vacchio, Melanie S., Castro, Ehydel, Tran, Bao, Tessarollo, Lino, Bosselut, Rémy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 38/15; 38/61; 42/41; 631/250/1619/554; 631/250/2152/1566/2493; 631/80/86; 64/60; 96/1; Animals; Cancer research; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cell division; Chromatin Immunoprecipitation; DNA methylation; Enzymes; Flow Cytometry; Gene expression; Histone Demethylases - genetics; Humanities and Social Sciences; In Vitro Techniques; Jumonji Domain-Containing Histone Demethylases - genetics; Life Sciences; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Real-Time Polymerase Chain Reaction; Receptors, Lysosphingolipid - metabolism; Science; Science (multidisciplinary); Stem cells; Thymocytes - cytology; Thymocytes - metabolism; Transcription factors; United States > US; Maryland
• DOI: 10.1038/ncomms9152
• ISSN: 2041-1723

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. Histone post-translational modifications such as the trimethylation of histone H3 at lysine 27 (H3K27Me3), affect DNA accessibility and transcription. Here, the authors show that Jmjd3 and Utx, two H3K27Me3 demethylases, are important for regulating the expression of genes involved in terminal thymocyte differentiation.