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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
Open accessAbstract
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, 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
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Metadata
- Authors
- Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G., & Rauscher, F. J.
- Affiliations
- The Wistar Institute (US)
- 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
- 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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