Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS UMR7104, Université de Strasbourg, Illkirch, France.
Eur J Immunol. 2010 Aug;40(8):2143-54. doi: 10.1002/eji.200940258.
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.
Bcl11b 是一种转录因子，在造血系统中特异性表达于 T 细胞。尽管 Bcl11b 在新生 Bcl11b 敲除小鼠的 T 细胞分化和成年小鼠胸腺中 T 细胞的阳性选择中是必需的，但 Bcl11b 在 T 细胞中调节的基因网络尚不清楚。我们在此报告，Bcl11b 是一种双功能转录调节因子，它是 CD4(+)CD8(+)CD3(lo)双阳性（DP）胸腺细胞中约 1000 个基因正确表达所必需的。Bcl11b 缺陷的 DP 细胞表现出与成熟 CD4(+)CD8(-)和 CD4(-)CD8(+)单阳性（SP）胸腺细胞相关的基因表达程序，包括关键转录调节因子如 Zbtb7b 和 Runx3 的上调。Bcl11b 与许多失调基因的调节区域相互作用，表明其在这些基因的转录调控中具有直接作用。然而，谱系相关基因的不当表达并未导致分化增强，因为 DP 细胞中 Bcl11b 的缺失阻止了 SP 胸腺细胞和经典 NKT 细胞的发育。这些数据确立了 Bcl11b 作为胸腺细胞中至关重要的转录调节因子，Bcl11b 在其中的功能是防止与 SP 和 NKT 细胞分化程序相关的基因的过早表达。
