Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favo...

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Bibliographic Details
Published in:Molecular and cellular biology 2019-07, Vol.39 (13)
Main Authors: McClellan, David, Casey, Mattie J., Bareyan, Diana, Lucente, Helena, Ours, Christopher, Velinder, Matthew, Singer, Jason, Lone, Mehraju Din, Sun, Wenxiang, Coria, Yunuen, Mason, Clinton C., Engel, Michael E.
Format: Article
Language:English
Subjects:
Animals
BHC complex
Cell Differentiation
Chlorocebus aethiops
COS Cells
Down-Regulation
Erythroid Cells - cytology
Erythroid Cells - metabolism
Erythropoiesis
GFI1B
GSE1
hematopoiesis
Histone Deacetylases - metabolism
Histone Demethylases - metabolism
HMG20A
HMG20B
Humans
K562 Cells
LSD1
Phenotype
Proto-Oncogene Proteins - metabolism
Repressor Proteins - metabolism
SNAG domain
Tetradecanoylphorbol Acetate - pharmacology
Transcription, Genetic
transcriptional repression
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Summary:Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1B's obligate effector, lysine-specific demethylase 1 (LSD1). We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin-remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2, and ZNF217) in an LSD1-dependent manner to control acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00020-19