RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function

RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function In human hematopoietic progenitors, RUNX1 and its partner CBFB are up-regulated at the onset of megakaryocytic differentiation and down-regulated at the onset of erythroid differentiation. The complex of RUNX1 and CBFB cooperates with the transcription factor GATA1 in the transactivation of megakaryocyte-specific genes. In addition, RUNX1 and GATA1 physically interact (Elagib et al. 2003), and this interaction involves the zinc finger domain of GATA1 (Xu et al. 2006). Other components of the RUNX1:CBFB activating complex at megakaryocytic promoters are GATA1 heterodimerization partner, ZFPM1 (FOG1), histone acetyltransferases EP300 (p300) and KAT2B (PCAF), the WDR5-containing histone methyltransferase MLL complex and the arginine methyltransferase PRMT1 (Herglotz et al. 2013). In the absence of PRMT1, the transcriptional repressor complex can form at megakaryocytic promoters, as RUNX1 that is not arginine methylated can bind to SIN3A/SIN3B co-repressors (Zhao et al. 2008). Besides SIN3A/SIN3B, the RUNX1:CBFB repressor complex at megakaryocytic promoters also includes histone deacetylase HDAC1 and histone arginine methyltransferase PRMT6 (Herglotz et al. 2013).
Megakaryocytic promoters regulated by the described RUNX1:CBFB activating and repressing complexes include ITGA2B, GP1BA, THBS1 and MIR27A (Herglotz et al. 2013). ITGA2B is only expressed in maturing megakaryocytes and platelets and is involved in platelet aggregation (Block and Poncz 1995). GP1BA is expressed at the cell surface membrane of maturing megakaryocytes and platelets and participates in formation of platelet plugs (Cauwenberghs et al. 2000, Jilma-Stohlawetz et al. 2003, Debili et al. 1990). THBS1 homotrimers contribute to stabilization of the platelet aggregate (Bonnefoy and Hoylaerts 2008). MIR27A is a negative regulator of RUNX1 mRNA translation and may be involved in erythroid/megakaryocytic lineage determination (Ben-Ami et al. 2009).
The RUNX1:CBFB complex stimulates transcription of the PF4 gene, encoding a component of platelet alpha granules (Aneja et al. 2011), the NR4A3 gene, associated with the familial platelet disorder (FPD) (Bluteau et al. 2011), the PRKCQ gene, associated with inherited thrombocytopenia (Jalagadugula et al. 2011), the MYL9 gene, involved in thrombopoiesis (Jalagadugula et al. 2010), and the NFE2 gene, a regulator of erythroid and megakaryocytic maturation and differentiation (Wang et al. 2010).