A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.
The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.
Lee
P P
PP
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Fitzpatrick
D R
DR
Beard
C
C
Jessup
H K
HK
Lehar
S
S
Makar
K W
KW
Pérez-Melgosa
M
M
Sweetser
M T
MT
Schlissel
M S
MS
Nguyen
S
S
Cherry
S R
SR
Tsai
J H
JH
Tucker
S M
SM
Weaver
W M
WM
Kelso
A
A
Jaenisch
R
R
Wilson
C B
CB
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology*; D019175:DNA Methylation; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse