PreprintCited by 1,313Genomics and Chromatin DynamicsEpigenetics and DNA MethylationCancer-related gene regulation

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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

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Schultz, David C., Ayyanathan, Kasirajan, Negorev, Dmitri, Maul, Gerd G., Rauscher, Frank J.·2002·Genes & Development

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Abstract

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.

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Authors: Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G., & Rauscher, F. J.
Affiliations: The Wistar Institute (US)
ORCID: Schultz, David C.
Ayyanathan, Kasirajan
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2002-04-15
Volume: 16
Issue: 8
Pages: 919-932
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.973302
PMC: PMC152359
OpenAlex: W2151026121
Cited by: 1,313
References: 44
Citations by year: 2026: 63 · 2025: 54 · 2024: 84 · 2023: 75 · 2022: 72 · 2021: 56 · 2020: 70 · 2019: 56 · 2018: 56 · 2017: 53 · 2016: 59 · 2015: 68 · 2014: 63 · 2013: 54 · 2012: 53
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Susan G. Komen for the Cure
Irving A. Hansen Memorial Foundation
National Institutes of Health (5r01gm054220-04, 10815, CA 10815)
National Cancer Institute (CA09171, CA-10815, CA92088, R01CA092088, T32CA009171, P30CA010815)
National Institute of General Medical Sciences (GM 54220)
National Institute of Allergy and Infectious Diseases (AI 41136, R56AI041136, R01AI041136)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords: SETDB1, KAP1, KRAB zinc finger proteins, H3K9 methylation, histone methyltransferase, HP1 proteins, heterochromatin formation, chromodomain, chromoshadow domain, histone acetylation, histone phosphorylation, transcriptional repression, SET domain
MeSH terms: Tripartite Motif-Containing Protein 28, Chromobox Protein Homolog 5, Animals, Cell Line, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Histones, Humans, Lysine, Methylation, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Histone-Lysine N-Methyltransferase, Protein Methyltransferases, Repressor Proteins, Substrate Specificity, Transcription Factors, Zinc Fingers, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Fluorescent Antibody Technique, Indirect, Two-Hybrid System Techniques, Gene Silencing, Euchromatin, Macromolecular Substances, Mice

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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

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