SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins

Posttranslational modification of histones has emerged as a key regulatory signal in eukaryotic gene expression. Recent genetic and biochemical studies link H3-lysine 9 (H3-K9) methylation to HP1-mediated heterochromatin formation and gene silencing. However, the mechanisms that target and coordinat...

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Bibliographic Details
Published in:Genes & development 2002-04, Vol.16 (8), p.919-932
Main Authors: Schultz, David C, Ayyanathan, Kasirajan, Negorev, Dmitri, Maul, Gerd G, Rauscher, 3rd, Frank J
Format: Article
Language:English
Subjects:
Animals
Cell Line
Chromosomal Proteins, Non-Histone - metabolism
DNA-Binding Proteins - metabolism
Euchromatin - metabolism
Fluorescent Antibody Technique, Indirect
Gene Silencing - physiology
Histones - metabolism
HP-1 gene
Humans
KAP-1 gene
Lysine - metabolism
Macromolecular Substances
Methylation
Mice
Molecular Sequence Data
Nuclear Proteins
Protein Binding - physiology
Protein Methyltransferases - genetics
Protein Methyltransferases - metabolism
Protein Structure, Tertiary - physiology
Repressor Proteins - metabolism
Research Paper
Sequence Homology, Amino Acid
SETDB1 gene
Substrate Specificity
Transcription Factors
Tripartite Motif-Containing Protein 28
Two-Hybrid System Techniques
Zinc Fingers
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Summary:Posttranslational modification of histones has emerged as a key regulatory signal in eukaryotic gene expression. Recent genetic and biochemical studies link H3-lysine 9 (H3-K9) methylation to HP1-mediated heterochromatin formation and gene silencing. However, the mechanisms that target and coordinate these activities to specific genes is poorly understood. Here we report that the KAP-1 corepressor for the KRAB-ZFP superfamily of transcriptional silencers binds to SETDB1, a novel SET domain protein with histone H3-K9-specific methyltransferase activity. Although acetylation and phosphorylation of the H3 N-terminal tail profoundly affect the efficiency of H3-K9 methylation by SETDB1, we found that methylation of H3-K4 does not affect SETDB1-mediated methylation of H3-K9. In vitro methylation of the N-terminal tail of histone H3 by SETDB1 is sufficient to enhance the binding of HP1 proteins, which requires both an intact chromodomain and chromoshadow domain. Indirect immunofluoresence staining of interphase nuclei localized SETDB1 predominantly in euchromatic regions that overlap with HP1 staining in nonpericentromeric regions of chromatin. Moreover, KAP-1, SETDB1, H3-MeK9, and HP1 are enriched at promoter sequences of a euchromatic gene silenced by the KRAB-KAP-1 repression system. Thus, KAP-1 is a molecular scaffold that is targeted by KRAB-ZFPs to specific loci and coordinates both histone methylation and the deposition of HP1 proteins to silence gene expression.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.973302