title: GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1.
abstract: 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 -(8)KSKK(11)- 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.
authors.affiliation: Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Matthew
authors.initials: M
authors.lastname: Velinder
authors.affiliation: Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Jason
authors.initials: J
authors.lastname: Singer
authors.affiliation: Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Diana
authors.initials: D
authors.lastname: Bareyan
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Primary Children's Hospital, Salt Lake City, UT, U.S.A.
authors.forename: Jessica
authors.initials: J
authors.lastname: Meznarich
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tracy
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: James M
authors.initials: JM
authors.lastname: Fulcher
authors.affiliation: Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: David
authors.initials: D
authors.lastname: McClellan
authors.affiliation: Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Helena
authors.initials: H
authors.lastname: Lucente
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Sarah
authors.initials: S
authors.lastname: Franklin
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT, U.S.A.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Primary Children's Hospital, Salt Lake City, UT, U.S.A. Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT, U.S.A. Nuclear Control of Cell Growth and Differentiation Program, Huntsman Cancer Institute, Salt Lake City, UT, U.S.A.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Engel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D019070:Cell Lineage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D014157:Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: GFI1; LSD1; cancer; epigenetics; methylation; transcription