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PMID:19497860

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Citation

Hu, X, Li, X, Valverde, K, Fu, X, Noguchi, C, Qiu, Y and Huang, S (2009) LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc. Natl. Acad. Sci. U.S.A. 106:10141-6

Abstract

TAL1 is a critical transcription factor required for hematopoiesis. However, perturbation of its activity often leads to T cell leukemia. Whether and how its transcriptional activities are regulated during hematopoiesis remains to be addressed. Here, we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. Finally, shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs.

Links

PubMed PMC2700898 Online version:10.1073/pnas.0900437106

Keywords

Basic Helix-Loop-Helix Transcription Factors/metabolism; Erythroid Cells/cytology; Erythroid Cells/enzymology; Erythropoiesis/genetics; Gene Knockdown Techniques; Gene Silencing; Histone Demethylases; Humans; Jurkat Cells; Oxidoreductases, N-Demethylating/genetics; Oxidoreductases, N-Demethylating/metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins/metabolism; Transcription, Genetic

Significance

Annotations

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

MOUSE:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P22091

F

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:KDM1A

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P22091

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60341-1

F

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15923

F

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01196

F

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99081

F

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q16576

F

Seeded From UniProt

complete

HUMAN:TAL1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O09106

F

Seeded From UniProt

complete

MOUSE:TAL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60341-1

F

Seeded From UniProt

complete

MOUSE:TAL1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TAL1

involved_in

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TAL1

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TAL1

involved_in

GO:0045648: positive regulation of erythrocyte differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RUNX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UKL0

F

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:RBBP7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

MOUSE:KDM1A

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KDM1A

enables

GO:1990841: promoter-specific chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:HTF4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17542

F

Seeded From UniProt

complete

HUMAN:RCOR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:TAL1

colocalizes_with

GO:0000118: histone deacetylase complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TAL1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60341

F

Seeded From UniProt

complete

HUMAN:TAL1

colocalizes_with

GO:0033193: Lsd1/2 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92769

F

Seeded From UniProt

complete

HUMAN:KDM1A

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KDM1A

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM1A

involved_in

GO:0043433: negative regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KDM1A

enables

GO:0032452: histone demethylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:KDM1A

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KDM1A

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KDM1A

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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