Bcl11b represses a mature T-cell gene expression program in immature CD4(+)CD8(+) thymocytes.
Bcl11b is a transcription factor that, within the hematopoietic system, is expressed specifically in T cells. Although Bcl11b is required for T-cell differentiation in newborn Bcl11b-null mice, and for positive selection in the adult thymus of mice bearing a T-cell-targeted deletion, the gene network regulated by Bcl11b in T cells is unclear. We report herein that Bcl11b is a bifunctional transcriptional regulator, which is required for the correct expression of approximately 1000 genes in CD4(+)CD8(+)CD3(lo) double-positive (DP) thymocytes. Bcl11b-deficient DP cells displayed a gene expression program associated with mature CD4(+)CD8(-) and CD4(-)CD8(+) single-positive (SP) thymocytes, including upregulation of key transcriptional regulators, such as Zbtb7b and Runx3. Bcl11b interacted with regulatory regions of many dysregulated genes, suggesting a direct role in the transcriptional regulation of these genes. However, inappropriate expression of lineage-associated genes did not result in enhanced differentiation, as deletion of Bcl11b in DP cells prevented development of SP thymocytes, and that of canonical NKT cells. These data establish Bcl11b as a crucial transcriptional regulator in thymocytes, in which Bcl11b functions to prevent the premature expression of genes fundamental to the SP and NKT cell differentiation programs.
Kastner
Philippe
P
Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS UMR7104, Université de Strasbourg, Illkirch, France. kastner@igbmc.fr
Chan
Susan
S
Vogel
Walter K
WK
Zhang
Ling-Juan
LJ
Topark-Ngarm
Acharawan
A
Golonzhka
Olga
O
Jost
Bernard
B
Le Gras
Stéphanie
S
Gross
Michael K
MK
Leid
Mark
M
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D050436:Regulatory Elements, Transcriptional / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D015704:CD4 Antigens; D016827:CD8 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C511143:Bcl11b protein, mouse; C497211:Zbtb7b protein, mouse