Kuvardina Olga N, Herglotz Julia, Kolodziej Stephan, Kohrs Nicole, Herkt Stefanie, Wojcik Bartosch, Oellerich Thomas, Corso Jasmin, Behrens Kira, Kumar Ashok, Hussong Helge, Urlaub Henning, Koch Joachim, Serve Hubert, Bonig Halvard, Stocking Carol, Rieger Michael A, Lausen Jörn
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
Blood. 2015 Jun 4;125(23):3570-9. doi: 10.1182/blood-2014-11-610519. Epub 2015 Apr 24.
The activity of antagonizing transcription factors represents a mechanistic paradigm of bidirectional lineage-fate control during hematopoiesis. At the megakaryocytic/erythroid bifurcation, the cross-antagonism of krueppel-like factor 1 (KLF1) and friend leukemia integration 1 (FLI1) has such a decisive role. However, how this antagonism is resolved during lineage specification is poorly understood. We found that runt-related transcription factor 1 (RUNX1) inhibits erythroid differentiation of murine megakaryocytic/erythroid progenitors and primary human CD34(+) progenitor cells. We show that RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation by epigenetic repression of the erythroid master regulator KLF1. RUNX1 binding to the KLF1 locus is increased during megakaryocytic differentiation and counterbalances the activating role of T-cell acute lymphocytic leukemia 1 (TAL1). We found that corepressor recruitment by RUNX1 contributes to a block of the KLF1-dependent erythroid gene expression program. Our data indicate that the repressive function of RUNX1 influences the balance between erythroid and megakaryocytic differentiation by shifting the balance between KLF1 and FLI1 in the direction of FLI1. Taken together, we show that RUNX1 is a key player within a network of transcription factors that represses the erythroid gene expression program.
拮抗转录因子的活性代表了造血过程中双向谱系命运控制的一种机制范式。在巨核细胞/红细胞分化分支点，类krueppel因子1（KLF1）和Friend白血病整合因子1（FLI1）的相互拮抗起着决定性作用。然而，在谱系特化过程中这种拮抗作用是如何解除的，目前还知之甚少。我们发现， runt相关转录因子1（RUNX1）抑制小鼠巨核细胞/红细胞祖细胞和原代人CD34(+)祖细胞的红细胞分化。我们表明，RUNX1通过对红细胞主调节因子KLF1的表观遗传抑制，在巨核细胞分化过程中抑制红细胞基因表达程序。在巨核细胞分化过程中，RUNX1与KLF1基因座的结合增加，并抵消了T细胞急性淋巴细胞白血病1（TAL1）的激活作用。我们发现，RUNX1募集共抑制因子有助于阻断KLF1依赖的红细胞基因表达程序。我们的数据表明，RUNX1的抑制功能通过将KLF1和FLI1之间的平衡向FLI1方向转移，影响红细胞和巨核细胞分化之间的平衡。综上所述，我们表明RUNX1是抑制红细胞基因表达程序的转录因子网络中的关键参与者。
