Biomedical subjects

Eric Lécuyer

Publications and source records attributed to Eric Lécuyer.

3 recordsLinked to original sources

PubMed2004

SCL: from the origin of hematopoiesis to stem cells and leukemia.

In the hematopoietic system, lineage commitment and differentiation is controlled by the combinatorial action of transcription factors from diverse families. SCL is a basic helix-loop-helix transcription factor that is an essential regulator at several levels in the hematopoietic hierarchy and whose inappropriate regulation frequently contributes to the development of pediatric T-cell acute lymphoblastic leukemia. This review discusses advances that have shed important light on the functions played by SCL during normal hematopoiesis and leukemogenesis and have revealed an unexpected robustness of hematopoietic stem cell function. Molecular studies have unraveled a mechanism through which gene expression is tightly controlled, as SCL functions within multifactorial complexes that exhibit an all-or-none switch-like behavior in transcription activation, arguing for a quantal process that depends on the concurrent occupation of target loci by all members of the complex. Finally, variations in composition of SCL-containing complexes may ensure flexibility and specificity in the regulation of lineage-specific programs of gene expression, thus providing the molecular basis through which SCL exerts its essential functions at several branch points of the hematopoietic hierarchy.

Animals↗

PubMed2004

SCL assembles a multifactorial complex that determines glycophorin A expression.

SCL/TAL1 is a hematopoietic-specific transcription factor of the basic helix-loop-helix (bHLH) family that is essential for erythropoiesis. Here we identify the erythroid cell-specific glycophorin A gene (GPA) as a target of SCL in primary hematopoietic cells and show that SCL occupies the GPA locus in vivo. GPA promoter activation is dependent on the assembly of a multifactorial complex containing SCL as well as ubiquitous (E47, Sp1, and Ldb1) and tissue-specific (LMO2 and GATA-1) transcription factors. In addition, our observations suggest functional specialization within this complex, as SCL provides its HLH protein interaction motif, GATA-1 exerts a DNA-tethering function through its binding to a critical GATA element in the GPA promoter, and E47 requires its N-terminal moiety (most likely entailing a transactivation function). Finally, endogenous GPA expression is disrupted in hematopoietic cells through the dominant-inhibitory effect of a truncated form of E47 (E47-bHLH) on E-protein activity or of FOG (Friend of GATA) on GATA activity or when LMO2 or Ldb-1 protein levels are decreased. Together, these observations reveal the functional complementarities of transcription factors within the SCL complex and the essential role of SCL as a nucleation factor within a higher-order complex required to activate gene GPA expression.

Adaptor Proteins, Signal Transducing↗

PubMed2002

The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1.

The combinatorial interaction among transcription factors is believed to determine hematopoietic cell fate. Stem cell leukemia (SCL, also known as TAL1 [T-cell acute lymphoblastic leukemia 1]) is a tissue-specific basic helix-loop-helix (bHLH) factor that plays a central function in hematopoietic development; however, its target genes and molecular mode of action remain to be elucidated. Here we show that SCL and the c-Kit receptor are coexpressed in hematopoietic progenitors at the single-cell level and that SCL induces c-kit in chromatin, as ectopic SCL expression in transgenic mice sustains c-kit transcription in developing B lymphocytes, in which both genes are normally down-regulated. Through transient transfection assays and coimmunoprecipitation of endogenous proteins, we define the role of SCL as a nucleation factor for a multifactorial complex (SCL complex) that specifically enhances c-kit promoter activity without affecting the activity of myelomonocytic promoters. This complex, containing hematopoietic-specific (SCL, Lim-only 2 (LMO2), GATA-1/GATA-2) and ubiquitous (E2A, LIM- domain binding protein 1 [Ldb-1]) factors, is tethered to DNA via a specificity protein 1 (Sp1) motif, through direct interactions between elements of the SCL complex and the Sp1 zinc finger protein. Furthermore, we demonstrate by chromatin immunoprecipitation that SCL, E2A, and Sp1 specifically co-occupy the c-kit promoter in vivo. We therefore conclude that c-kit is a direct target of the SCL complex. Proper activation of the c-kit promoter depends on the combinatorial interaction of all members of the complex. Since SCL is down-regulated in maturing cells while its partners remain expressed, our observations suggest that loss of SCL inactivates the SCL complex, which may be an important event in the differentiation of pluripotent hematopoietic cells.

3T3 Cells↗