Identification of an N-terminal Transactivation Domain of Runx1 That Separates Molecular Function from Global Differentiation Function
Overview
Authors
Affiliations
RUNX1, or AML1, is a transcription factor that is the most frequent target for chromosomal gene translocations in acute leukemias. RUNX1 is essential for definitive hematopoiesis in embryos and profoundly influences adult steady-state hematopoiesis both positively and negatively. To investigate this wide range of normal activities and the pathological role of RUNX1, it is important to define the functions of different domains of the protein. RUNX1, RUNX2, and RUNX3 are highly conserved in their DNA binding runt homology domain and contain divergent sequences of unknown function N-terminal to this domain. Here we analyzed the role of the N-terminal sequence and the alpha-helix of the runt homology domain of Runx1 in DNA binding, transactivation, and megakaryocytopoiesis. Both the N terminus and the alpha-helix were found to reduce DNA binding of Runx1 and be essential for transactivation of the granulocyte-macrophage colony-stimulating factor and Ialpha1 promoters by Runx1. The N terminus of Runx1, including the alpha-helix, was also required for transactivation of a Gal4 reporter when expressed as fusion proteins with a Gal4 DNA binding domain, and the N terminus alone was capable of stimulating transcription when fused to the Gal4 DNA binding domain. The N terminus and the alpha-helix, however, were not required for megakaryocyte development from embryonic stem cells differentiated in vitro. Thus, our findings define a second transactivation domain of Runx1 that is differentially required for activation of transcription of some Runx1-dependent promoters and megakaryocytopoiesis.
RUNX1 Dosage in Development and Cancer.
Lie-A-Ling M, Mevel R, Patel R, Blyth K, Baena E, Kouskoff V Mol Cells. 2020; 43(2):126-138.
PMID: 31991535 PMC: 7057845. DOI: 10.14348/molcells.2019.0301.
Luo X, Feurstein S, Mohan S, Porter C, Jackson S, Keel S Blood Adv. 2019; 3(20):2962-2979.
PMID: 31648317 PMC: 6849945. DOI: 10.1182/bloodadvances.2019000644.
Loss of function results in B cell immunodeficiency but not T cell in adult zebrafish.
Chi Y, Huang Z, Chen Q, Xiong X, Chen K, Xu J Open Biol. 2018; 8(7).
PMID: 30045885 PMC: 6070721. DOI: 10.1098/rsob.180043.
Rahmanian N, Tarighi P, Gharghabi M, Torshabi M, Tarfiei G, Mohammadi Farsani T Iran J Pharm Res. 2017; 16(3):1194-1203.
PMID: 29201108 PMC: 5610775.
H19-derived miR-675 contributes to bladder cancer cell proliferation by regulating p53 activation.
Liu C, Chen Z, Fang J, Xu A, Zhang W, Wang Z Tumour Biol. 2015; 37(1):263-70.
PMID: 26198047 PMC: 4841850. DOI: 10.1007/s13277-015-3779-2.