Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation.
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.
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Sugata
S
Manna
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jong Kyong
JK
Kim
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Catherine
C
Baugé
Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Margaret
M
Cam
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
Yongmei
Y
Zhao
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
Jyoti
J
Shetty
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Melanie S
MS
Vacchio
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ehydel
E
Castro
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
Bao
B
Tran
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Lino
L
Tessarollo
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Rémy
R
Bosselut
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D056466:Histone Demethylases / Q000235:genetics*; D066298:In Vitro Techniques; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D060168:Thymocytes / Q000166:cytology* / Q000378:metabolism
D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C111778:Utx protein, mouse; C523761:Kdm6b protein, mouse