Human THAP7 is a chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor

Todd Macfarlan, Sara Kutney, Brian Altman, Rebecca Montross, Jiujiu Yu, Debabrata Chakravarti

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The identities of signal transducer proteins that integrate histone hypoacetylation and transcriptional repression are largely unknown. Here we demonstrate that THAP7, an uncharacterized member of the recently identified THAP (Thanatos-associated protein) family of proteins, is ubiquitously expressed, associates with chromatin, and represses transcription. THAP7 binds preferentially to hypoacetylated (un-, mono-, and di-acetylated) histone H4 tails in vitro via its C-terminal 77 amino acids. Deletion of this domain, or treatment of cells with the histone deacetylase inhibitor TSA, which leads to histone hyperacetylation, partially disrupts THAP7/ chromatin association in living cells. THAP7 coimmunoprecipitates with histone deacetylase 3 (HDAC3) and the nuclear hormone receptor corepressor (NCoR) and represses transcription as a Gal4 fusion protein. Chromatin immunoprecipitation assays demonstrate that these corepressors are recruited to promoters in a THAP7 dependent manner and promote histone H3 hypoacetylation. The conserved THAP domain is a key determinant for full HDAC3 association in vitro, and both the THAP domain and the histone interaction domain are important for the repressive properties of THAP7. Full repression mediated by THAP7 is also dependent on NCoR expression. We hypothesize that THAP7 is a dual function repressor protein that actively targets deacetylation of histone H3 necessary to establish transcriptional repression and functions as a signal transducer of the repressive mark of hypoacetylated histone H4. This is the first demonstration of the transcriptional regulatory properties of a human THAP domain protein, and a critical identification of a potential transducer of the repressive signal of hypoacetylated histone H4 in higher eukaryotes.

Original languageEnglish (US)
Pages (from-to)7346-7358
Number of pages13
JournalJournal of Biological Chemistry
Volume280
Issue number8
DOIs
StatePublished - Feb 25 2005

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Co-Repressor Proteins
Transcription
Cytoplasmic and Nuclear Receptors
Histones
Chromatin
Tail
Carrier Proteins
Proteins
Transducers
Cells
Association reactions
Protein Interaction Domains and Motifs
Repressor Proteins
Histone Deacetylase Inhibitors
histone deacetylase 3
Chromatin Immunoprecipitation
Eukaryota
Assays
Demonstrations
Fusion reactions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Human THAP7 is a chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor. / Macfarlan, Todd; Kutney, Sara; Altman, Brian; Montross, Rebecca; Yu, Jiujiu; Chakravarti, Debabrata.

In: Journal of Biological Chemistry, Vol. 280, No. 8, 25.02.2005, p. 7346-7358.

Research output: Contribution to journalArticle

Macfarlan, Todd ; Kutney, Sara ; Altman, Brian ; Montross, Rebecca ; Yu, Jiujiu ; Chakravarti, Debabrata. / Human THAP7 is a chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 8. pp. 7346-7358.
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