title: Erythroid-specific inhibition of the tal-1 intragenic promoter is due to binding of a repressor to a novel silencer.
abstract: 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 NH(2)-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'-untranslated 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.
authors.affiliation: Institut de Génétique Moléculaire, UMR 5535, IFR 24, 1919 Route de Mende, F 34293, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Courtes
authors.forename: N
authors.initials: N
authors.lastname: Lecointe
authors.forename: L
authors.initials: L
authors.lastname: Le Cam
authors.forename: F
authors.initials: F
authors.lastname: Baudoin
authors.forename: C
authors.initials: C
authors.lastname: Sardet
authors.forename: D
authors.initials: D
authors.lastname: Mathieu-Mahul
mesh_terms: D016475:3T3 Cells; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005091:Exons; D020868:Gene Silencing; D006367:HeLa Cells; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D020014:K562 Cells; D015458:Leukemia, T-Cell / Q000235:genetics; D008533:Megakaryocytes / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D020121:5' Untranslated Regions; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human