Abstract
LMO2 is a bridging factor within a DNA binding complex and is required for definitive haematopoiesis to occur. The developmental stage of the block in haematopoietic specification is not known. We show that Lmo2−/− mouse embryonic stem cells differentiated to Flk-1+ haemangioblasts, but less efficiently to haemogenic endothelium, which only produced primitive haematopoietic progenitors. Genome-wide approaches indicated that LMO2 is required at the haemangioblast stage to position the TAL1/LMO2/LDB1 complex to regulatory elements that are important for the establishment of the haematopoietic developmental program. In the absence of LMO2, the target site recognition of TAL1 is impaired. The lack of LMO2 resulted in altered gene expression levels already at the haemangioblast stage, with transcription factor genes accounting for ∼15% of affected genes. Comparison of Lmo2−/− with Tal1−/− Flk-1+ cells further showed that TAL1 was required to initiate or sustain Lmo2 expression.
Highlights
LIM only 2 (LMO2) was originally identified through its homology to LMO1 and was shown to cause T-cell acute lymphoblastic leukaemia, as a consequence of chromosomal translocations involving LMO2 and the T-cell receptor genes [1]
Haemangioblasts were enriched by isolating Flk-1+ (VEGFR2) cells, which were subsequently either used for analysis, or further cultured in blast medium for the formation of haemogenic endothelium 1 (HE1; Tie2+, Kit+, CD41−), and via haemogenic endothelium 2 (HE2; Tie2+, Kit+, CD41+) to haematopoietic progenitors (Tie2−, Kit+/−, CD41+)
Expression of Lmo2 was first detected in the early Flk-1+ cells, isolated at day 3.0 and was increased in Flk-1+ cells isolated at day 3.75
Summary
LIM only 2 (LMO2) was originally identified through its homology to LMO1 and was shown to cause T-cell acute lymphoblastic leukaemia, as a consequence of chromosomal translocations involving LMO2 and the T-cell receptor genes [1]. The first LMO2 protein complex was characterised in the erythroid lineage and besides LMO2 contains the transcription factors TAL1, E2A, LDB1 and GATA1. LMO2 links the DNA binding TAL1-E2A dimer with GATA1, as well as with LDB1 [2]. Further research in erythroid cells identified more components of this complex and their dynamic changes during differentiation [6]. Other variants of the DNA binding factors within the LMO2-containing protein complexes have been reported, where GATA1 is replaced by GATA-2 [7,8], GATA3 [9] or a second TAL1-E2A dimer [10], as well as interactions with a number of other transcription factors [7,11]
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