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PMID:17707228

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Citation

Saleque, S, Kim, J, Rooke, HM and Orkin, SH (2007) Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol. Cell 27:562-72

Abstract

Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse developmental contexts, including hematopoiesis and oncogenesis. Transcriptional repression by Gfi proteins requires the conserved SNAG domain. To elucidate the function of Gfi proteins, we purified Gfi-1b complexes and identified interacting proteins. Prominent among these is the corepressor CoREST, the histone demethylase LSD1, and HDACs 1 and 2. CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain. Gfi-1b further recruits these cofactors to the majority of target gene promoters in vivo. Inhibition of CoREST and LSD1 perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as well as primary erythroid progenitors. LSD1 depletion derepresses Gfi targets in lineage-specific patterns, accompanied by enhanced histone 3 lysine 4 methylation at the respective promoters. Overall, we show that chromatin regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi proteins. Lineage-restricted deployment of these cofactors through interaction with Gfi proteins controls hematopoietic differentiation.

Links

PubMed Online version:10.1016/j.molcel.2007.06.039

Keywords

Amino Acid Sequence; Animals; Cell Differentiation/genetics; Cell Line, Tumor; Cell Lineage; DNA Methylation; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/metabolism; Epigenesis, Genetic; Erythroid Cells/cytology; Hematopoiesis/genetics; Histone Deacetylases/metabolism; Histones/metabolism; Mice; Models, Genetic; Molecular Sequence Data; Multiprotein Complexes/metabolism; Nerve Tissue Proteins/metabolism; Oxidoreductases, N-Demethylating/deficiency; Oxidoreductases, N-Demethylating/metabolism; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins/chemistry; Proto-Oncogene Proteins/metabolism; RNA Interference; Repressor Proteins/chemistry; Repressor Proteins/metabolism; Transcription Factors/chemistry; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HDAC1

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GFI1B

involved_in

GO:0030854: positive regulation of granulocyte differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GFI1B

involved_in

GO:0051574: positive regulation of histone H3-K9 methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GFI1B

involved_in

GO:0051572: negative regulation of histone H3-K4 methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GFI1B

involved_in

GO:0045646: regulation of erythrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GFI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CFE3

F

Seeded From UniProt

complete

MOUSE:RCOR1

involved_in

GO:0030218: erythrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RCOR1

involved_in

GO:0045654: positive regulation of megakaryocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RCOR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70338

F

Seeded From UniProt

complete

MOUSE:HDAC1

part_of

GO:0005667: transcription factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KDM1A

involved_in

GO:0010725: regulation of primitive erythrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM1A

involved_in

GO:0045648: positive regulation of erythrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM1A

involved_in

GO:0030851: granulocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM1A

involved_in

GO:0045654: positive regulation of megakaryocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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