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

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

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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  • SETDB1 deposits the repressive H3K9me3 mark and contributes to mood regulation through its control of cortical inhibitory interneurons.

    “SETDB1, a histone methyltransferase that deposits the repressive H3K9me3 mark, also contributes to mood regulation through its control of cortical inhibitory interneurons (Karimi et al., 2011) (Schultz et al., 2002; Minkovsky et al., 2014; Matsui et al., 2010).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Schultz et al., 2002

    The section “SETDB1 is a highly selective H3-K9 methyltransferase” (page unavailable) shows that SETDB1 methylates histone H3 at lysine 9, and “Mechanism of K9 methylation” links that mark to repression. The copy does not establish the specific trimethylated state, H3K9me3, or address mood regulation or cortical inhibitory interneurons. (LLM, conf=0.88)

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Authors
Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G., & Rauscher, F. J.
Affiliations
The Wistar Institute (US)
Venue
Genes & Development
Published
2002-04-15
Volume
16
Issue
8
Pages
919-932
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
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
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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