Proper hematopoietic cell fate decisions require co-ordinated functions of transcription factors, their associated co-regulators, and histone-modifying enzymes. Growth factor independence 1 (GFI1) is a zinc finger transcriptional repressor and master regulator of normal and malignant hematopoiesis. While several GFI1-interacting proteins have been described, how GFI1 leverages these relationships to carry out transcriptional repression remains unclear. Here, we describe a functional axis involving GFI1, SMYD2, and LSD1 that is a critical contributor to GFI1-mediated transcriptional repression. SMYD2 methylates lysine-8 (K8) within a -8KSKK11- motif embedded in the GFI1 SNAG domain. Methylation-defective GFI1 SNAG domain lacks repressor function due to failure of LSD1 recruitment and persistence of promoter H3K4 di-methyl marks. Methylation-defective GFI1 also fails to complement GFI1 depletion phenotypes in developing zebrafish and lacks pro-growth and survival functions in lymphoid leukemia cells. Our data show a discrete methylation event in the GFI1 SNAG domain that facilitates recruitment of LSD1 to enable transcriptional repression and co-ordinate control of hematopoietic cell fate in both normal and malignant settings.
GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1
Matthew Velinder, Jason Singer, Diana Bareyan, Jessica Meznarich, Christopher M. Tracy, James M. Fulcher, David McClellan, Helena Lucente, Sarah Franklin, Sunil Sharma, Michael E. Engel; GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1. Biochem J 1 October 2016; 473 (19): 3355–3369. doi: https://doi.org/10.1042/BCJ20160558
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