Human CD1D Gene Expression Is Regulated by LEF-1 through Distal Promoter Regulatory Elements

Abstract

CD1d-expressing cells present lipid Ag to CD1d-restricted NKT cells, which play an important role in immune regulation and tumor rejection. Lymphoid enhancer-binding factor-1 (LEF-1) is one of the regulators of the Wnt signaling pathway, which is a powerful regulator in cellular growth, differentiation, and transformation. There is little evidence connecting Wnt signaling to CD1d expression. In this study, we have identified LEF-1 as a regulator of the expression of the gene encoding the human CD1d molecule (CD1D). We found that LEF-1 binds specifically to the CD1D promoter. Overexpression of LEF-1 in K562 or Jurkat cells suppresses CD1D promoter activity and downregulates endogenous CD1D transcripts, whereas knockdown of LEF-1 using LEF-1-specific small interfering RNA increases CD1D transcripts in K562 and Jurkat cells but there are different levels of surface CD1d on these two cell types. Chromatin immunoprecipitation showed that the endogenous LEF-1 is situated at the CD1D promoter and interacts with histone deacetylase-1 to facilitate the transcriptional repressor activity. Knockdown of LEF-1 using small interfering RNA potentiates an acetylation state of histone H3/H4, supporting the notion that LEF-1 acts as a transcriptional repressor for the CD1D gene. Our finding links LEF-1 to CD1D and suggests a role of Wnt signaling in the regulation of the human CD1D gene.

The Diagnostic Value of CD1d Expression in a Large Cohort of Patients With B-Cell Chronic Lymphoproliferative Disorders

“…35 LEF-1 is highly (Image 1A). It has been recently suggested that SMZL and HCL may originate from a circulating IgM+/IgD+/CD27+ B cell derived from the splenic marginal zone that has acquired somatic hypermutations in the absence of germinal center reactions.…”

Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

“…Although LEF1 is best known for its role in WNT/b-catenin signaling, there is evidence that it can also function independent of b-catenin in transcription regulation, and these functions are induced by the HMG domain or by its interaction with alternative cofactors. [28][29][30][31] It will be of great interest to assess these alternative mechanisms of action of LEF1 in chronic lymphocytic leukemia. Recently, several pharmacological inhibitors or small molecules have been shown to efficiently induce apoptosis of chronic lymphocytic leukemia cells in vitro through their interaction with LEF1.…”

Innate immune control of EBV-infected B cells by invariant natural killer T cells

“…RARa is thought to modulate CD1d expression by altering the activity of LEF-1, a nuclear protein that associates with translocated b-catenin and binds to the distal region of the CD1d promoter. [29][30][31] Furthermore, overexpression of LEF-1 in both K562 and Jurkat human leukemia T-cell lines silences the human CD1d promoter activity, suggesting that higher levels of LEF-1 expression in LCL may also downregulate CD1d expression. 30 Given that EBV transformation of B cells resulted in a loss of CD1d that could be restored with AM580, we hypothesized that CD1d expression in LCL is silenced by the binding of LEF-1/ b-catenin complex to the CD1d distal promoter on EBV infection and that AM580 treatment restores CD1d expression by inhibiting the accumulation of LEF-1 at the CD1d promoter.…”