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.
Highlights
Histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive
S1pr[1] expression was not rescued by Uty in male cells lacking both Jmjd[3] and Utx, supporting the idea that it requires Jmjd3- or Utx-catalyzed H3K27Me3 demethylation at its promoter. These findings demonstrate that Jmjd[3] and Utx are required for T-cell differentiation
Jmjd[3] and Utx are important for T-cell development
Summary
Histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive. Thymocyte expression of S1pr[1] 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. H3K27 demethylases Jmjd[3] and Utx has suggested that active demethylation contributes to the depletion of H3K27Me3 and to initiation of lineage-specific gene expression[9,10,11,12,13] Whereas both molecules are necessary during mouse embryonic or postnatal development[14,15,16,17,18,19], it has remained unclear whether such biological functions involve their demethylase activity
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