Stanulovic Vesna S, Cauchy Pierre, Assi Salam A, Hoogenkamp Maarten
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Nucleic Acids Res. 2017 Sep 29;45(17):9874-9888. doi: 10.1093/nar/gkx573.
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.
LMO2是一种DNA结合复合物中的桥梁因子，是确定性造血发生所必需的。造血特化过程中阻滞的发育阶段尚不清楚。我们发现，Lmo2基因敲除的小鼠胚胎干细胞可分化为Flk-1+成血管细胞，但向造血内皮细胞的分化效率较低，后者仅产生原始造血祖细胞。全基因组方法表明，在成血管细胞阶段需要LMO2将TAL1/LMO2/LDB1复合物定位到对建立造血发育程序很重要的调控元件上。在没有LMO2的情况下，TAL1的靶位点识别受损。LMO2的缺失在成血管细胞阶段就导致了基因表达水平的改变，其中转录因子基因约占受影响基因的15%。将Lmo2基因敲除的细胞与Tal1基因敲除的Flk-1+细胞进行比较，进一步表明TAL1是启动或维持Lmo2表达所必需的。
