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
- Views Icon Views
- Share Icon Share
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
Download citation file: