Erythroid-specific Inhibition of the tal-1 Intragenic Promoter Is Due to Binding of a Repressor to a Novel Silencer

• Published in: The Journal of biological chemistry 2000-01, Vol.275 (2), p.949-958
• Main Authors: Courtes, Christine, Lecointe, Nathalie, Le Cam, Laurent, Baudoin, Florence, Sardet, Claude, Mathieu-Mahul, Danièle
• Format: Article
• Language: English
• Subjects: 3T3 Cells; 5' Untranslated Regions - genetics; Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Binding Sites; Biochemistry, Molecular Biology; Cell Line; Consensus Sequence; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Exons; Gene Silencing; Genomics; HeLa Cells; Helix-Loop-Helix Motifs; Humans; K562 Cells; Leukemia, T-Cell - genetics; Life Sciences; Megakaryocytes - metabolism; Mice; Molecular Sequence Data; Promoter Regions, Genetic; Proto-Oncogene Proteins; Regulatory Sequences, Nucleic Acid; Repressor Proteins; Sequence Alignment; Sequence Homology, Nucleic Acid; T-Cell Acute Lymphocytic Leukemia Protein 1; T-Lymphocytes - metabolism; tal-1 gene; TAL-1 protein; Transcription Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.275.2.949

The basic helix-loop-helix tal-1 gene plays a key role in hematopoiesis, and its expression is tightly controlled through alternative promoters and complex interactions of cis-acting regulatory elements. tal-1 is not expressed in normal T cells, but its transcription is constitutive in a large proportion of human T cell leukemias. We have previously described a downstream initiation of tal-1 transcription specifically associated with a subset of T cell leukemias that leads to the production of NH2-truncated TAL-1 proteins. In this study, we characterize the human promoter (promoter IV), embedded within a GC-rich region in exon IV, responsible for this transcriptional activity. The restriction of promoter IV usage is assured by a novel silencer element in the 3′-unstranslated region of the human gene that represses its activity in erythroid but not in T cells. The silencer activity is mediated through binding of a tissue-specific nuclear factor to a novel protein recognition motif (designated tal-RE) in the silencer. Mutation of a single residue within the tal-RE abolishes both specific protein binding and silencing activity. Altogether, our results demonstrate that the tal-1 promoter IV is actively repressed in cells of the erythro-megakaryocytic lineage and that this repression is released in leukemic T cells, resulting in the expression of the tal-1 truncated transcript.