RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function

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R-HSA-8936459
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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
19114653 A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis

Ben-Ami, O, Pencovich, N, Lotem, J, Levanon, D, Groner, Y

Proc. Natl. Acad. Sci. U.S.A. 2009
11132103 Structural determinants within platelet glycoprotein Ibalpha involved in its binding to von Willebrand factor

Cauwenberghs, N, Vanhoorelbeke, K, Vauterin, S, Deckmyn, H

Platelets 2000
12588352 Glycoprotein Ib polymorphisms influence platelet plug formation under high shear rates

Jilma-Stohlawetz, P, Homoncik, M, Jilma, B, Knechtelsdorfer, M, Unger, P, Mannhalter, C, Santoso, S, Panzer, S

Br. J. Haematol. 2003
20339092 AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2

Wang, W, Schwemmers, S, Hexner, EO, Pahl, HL

Blood 2010
20876458 Regulation of platelet myosin light chain (MYL9) by RUNX1: implications for thrombocytopenia and platelet dysfunction in RUNX1 haplodeficiency

Jalagadugula, G, Mao, G, Kaur, G, Goldfinger, LE, Dhanasekaran, DN, Rao, AK

Blood 2010
21252065 Platelet protein kinase C-theta deficiency with human RUNX1 mutation: PRKCQ is a transcriptional target of RUNX1

Jalagadugula, G, Mao, G, Kaur, G, Dhanasekaran, DN, Rao, AK

Arterioscler. Thromb. Vasc. Biol. 2011
18855616 Thrombospondin-1 in von Willebrand factor function

Bonnefoy, A, Hoylaerts, MF

Curr Drug Targets 2008
21129147 Mechanism of platelet factor 4 (PF4) deficiency with RUNX1 haplodeficiency: RUNX1 is a transcriptional regulator of PF4

Aneja, K, Jalagadugula, G, Mao, G, Singh, A, Rao, AK

J. Thromb. Haemost. 2011
18316480 Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity

Zhao, X, Jankovic, V, Gural, A, Huang, G, Pardanani, A, Menendez, S, Zhang, J, Dunne, R, Xiao, A, Erdjument-Bromage, H, Allis, CD, Tempst, P, Nimer, SD

Genes Dev. 2008
21725049 Down-regulation of the RUNX1-target gene NR4A3 contributes to hematopoiesis deregulation in familial platelet disorder/acute myelogenous leukemia

Bluteau, D, Gilles, L, Hilpert, M, Antony-Debré, I, James, C, Debili, N, Camara-Clayette, V, Wagner-Ballon, O, Cordette-Lagarde, V, Robert, T, Ripoche, H, Gonin, P, Swierczek, S, Prchal, J, Vainchenker, W, Favier, R, Raslova, H

Blood 2011
12576332 RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation

Elagib, KE, Racke, FK, Mogass, M, Khetawat, R, Delehanty, LL, Goldfarb, AN

Blood 2003
2196092 Expression of platelet glycoprotein Ib by cultured human megakaryocytes: ultrastructural localization and biosynthesis

Debili, N, Kieffer, N, Nakazawa, M, Guichard, J, Titeux, M, Cramer, E, Breton-Gorius, J, Vainchenker, W

Blood 1990
16628190 Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblastic leukemia accompanying Down syndrome

Xu, G, Kanezaki, R, Toki, T, Watanabe, S, Takahashi, Y, Terui, K, Kitabayashi, I, Ito, E

Leukemia 2006
7787779 Platelet glycoprotein IIb gene expression as a model of megakaryocyte-specific expression

Block, KL, Poncz, M

Stem Cells 1995
22777353 Histone arginine methylation keeps RUNX1 target genes in an intermediate state

Herglotz, J, Kuvardina, ON, Kolodziej, S, Kumar, A, Hussong, H, Grez, M, Lausen, J

Oncogene 2013
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