PUBLICATION
GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1
- Authors
- Velinder, M., Singer, J., Bareyan, D., Meznarich, J., Tracy, C.M., Fulcher, J.M., McClellan, D., Lucente, H., Franklin, S., Sharma, S., Engel, M.E.
- ID
- ZDB-PUB-160804-24
- Date
- 2016
- Source
- The Biochemical journal 473(19): 3355-69 (Journal)
- Registered Authors
- Keywords
- GFI1, LSD1, cancer, epigenetics, methylation, transcription
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Cell Line
- Cell Lineage
- DNA Methylation
- DNA-Binding Proteins/chemistry
- DNA-Binding Proteins/physiology*
- Histone Demethylases/metabolism*
- Humans
- Sequence Homology, Amino Acid
- Transcription Factors/chemistry
- Transcription Factors/physiology*
- Transcription, Genetic/physiology*
- Zebrafish
- PubMed
- 27480105 Full text @ Biochem. J.
Citation
Velinder, M., Singer, J., Bareyan, D., Meznarich, J., Tracy, C.M., Fulcher, J.M., McClellan, D., Lucente, H., Franklin, S., Sharma, S., Engel, M.E. (2016) GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1. The Biochemical journal. 473(19):3355-69.
Abstract
Proper hematopoietic cell fate decisions require coordinated 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 coordinate control of hematopoietic cell fate in both normal and malignant settings.
Errata / Notes
This article is corrected by ZDB-PUB-220906-79 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping