Manna Sugata, Kim Jong Kyong, Baugé Catherine, Cam Margaret, Zhao Yongmei, Shetty Jyoti, Vacchio Melanie S, Castro Ehydel, Tran Bao, Tessarollo Lino, Bosselut Rémy
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Commun. 2015 Sep 2;6:8152. doi: 10.1038/ncomms9152.
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.
虽然组蛋白H3赖氨酸27三甲基化（H3K27Me3）与基因沉默相关，但H3K27Me3去甲基化是否在体内影响转录和细胞分化仍不清楚。为了研究这一问题，我们在非分裂的胸腺内CD4(+) T细胞前体中条件性失活了两种H3K27Me3去甲基化酶Jmjd3和Utx。我们在此表明，这两种酶在促进参与终末胸腺细胞分化的特定基因子集的H3K27Me3去除及其表达方面存在冗余作用，尤其是S1pr1，它编码胸腺细胞迁出所需的一种鞘氨醇-1-磷酸受体。在携带催化失活的Utx同源物Uty的Jmjd3和Utx缺陷型雄性小鼠中，胸腺细胞S1pr1的表达未得到挽救，这支持了其需要H3K27Me3去甲基化酶活性的结论。这些发现表明Jmjd3和Utx是T细胞发育所必需的，并指出它们的H3K27Me3去甲基化酶活性在细胞分化中是必需的。
