Runx proteins regulate Foxp3 expression.
Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of Foxp3 during inducible T reg cell differentiation, whereas the isolated dominant-negative Runt DNA binding domain antagonized de novo Foxp3 expression. Foxp3 expression in natural T reg cells remained dependent on Runx proteins and correlated with the binding of Runx/core-binding factor beta to regulatory elements within the Foxp3 locus. Our data show that Runx and Foxp3 are components of a feed-forward loop in which Runx proteins contribute to the expression of Foxp3 and cooperate with Foxp3 proteins to regulate the expression of downstream target genes.
Bruno
Ludovica
L
Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London W12 0NN, England, UK.
Mazzarella
Luca
L
Hoogenkamp
Maarten
M
Hertweck
Arnulf
A
Cobb
Bradley S
BS
Sauer
Stephan
S
Hadjur
Suzana
S
Leleu
Marion
M
Naoe
Yoshinori
Y
Telfer
Janice C
JC
Bonifer
Constanze
C
Taniuchi
Ichiro
I
Fisher
Amanda G
AG
Merkenschlager
Matthias
M
D000818:Animals; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000737:chemistry / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005799:Genes, Dominant; D051379:Mice; D017434:Protein Structure, Tertiary; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
C493693:Cbfb protein, mouse; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C493730:Runx3 protein, mouse