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PMID:17636019

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Citation

Duan, Z, Person, RE, Lee, HH, Huang, S, Donadieu, J, Badolato, R, Grimes, HL, Papayannopoulou, T and Horwitz, MS (2007) Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5. Mol. Cell. Biol. 27:6889-902

Abstract

Gfi1 transcriptionally governs hematopoiesis, and its mutations produce neutropenia. In an effort to identify Gfi1-interacting proteins and also to generate new candidate genes causing neutropenia, we performed a yeast two-hybrid screen with Gfi1. Among other Gfi1-interacting proteins, we identified a previously uncharacterized member of the PR domain-containing family of tumor suppressors, PRDM5. PRDM5 has 16 zinc fingers, and we show that it acts as a sequence-specific, DNA binding transcription factor that targets hematopoiesis-associated protein-coding and microRNA genes, including many that are also targets of Gfi1. PRDM5 epigenetically regulates transcription similarly to Gfi1: it recruits the histone methyltransferase G9a and class I histone deacetylases to its target gene promoters and demonstrates repressor activity on synthetic reporters; on endogenous target genes, however, it functions as an activator, in addition to a repressor. Interestingly, genes that PRDM5 activates, as opposed to those it represses, are also targets of Gfi1, suggesting a competitive mechanism through which two repressors could cooperate in order to become transcriptional activators. In neutropenic patients, we identified PRDM5 protein sequence variants perturbing transcriptional function, suggesting a potentially important role in hematopoiesis.

Links

PubMed PMC2099216 Online version:10.1128/MCB.00762-07

Keywords

Cell Cycle/physiology; Cell Line; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Epigenesis, Genetic; Gene Expression Regulation; Hematopoiesis/physiology; Histone Deacetylase 1; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Histone-Lysine N-Methyltransferase/metabolism; Humans; MicroRNAs/genetics; MicroRNAs/metabolism; Molecular Sequence Data; Neutropenia/genetics; Neutropenia/metabolism; Promoter Regions, Genetic; Protein Methyltransferases; RNA Interference; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Two-Hybrid System Techniques; Zinc Fingers

Significance

Annotations

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

HUMAN:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NQX1

F

Seeded From UniProt

complete

HUMAN:EHMT2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NQX1

F

Seeded From UniProt

complete

HUMAN:GFI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NQX1

F

Seeded From UniProt

complete

HUMAN:PRDM5

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

HUMAN:PRDM5

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96KQ7

F

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99684

F

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:PRDM5

involved_in

GO:0016575: histone deacetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRDM5

involved_in

GO:0000278: mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRDM5

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRDM5

involved_in

GO:0051567: histone H3-K9 methylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0140297: DNA-binding transcription factor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PRDM5

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PRDM5

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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