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.

By D. C. Schultz, K. Ayyanathan, D. Negorev, G. Maul, F. Rauscher. Genes & Development, 2002

1,285 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/485e94cb854ec7808ce89419bfb5a0feb2f23643

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Citations in the corpus

G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. (2002, background): “To date, the catalytically defined set of H3-K9 HMTases in mammals consists of Suv39h (1 and 2) (O’Carroll et al. 2000; Rea et al. 2000), ESET (Schultz et al. 2002; Yang et al. 2002), and G9a.”
An Integrated Encyclopedia of DNA Elements in the Human Genome (2012, background): “These are regions around the DBX1 (from SOM unit 26,31, left panel) and IRX6 (SOM unit 27,30, right panel) genes, respectively, along with their H3K27me3 ChIP-seq signal for each of the Tier 1 and 2 cell types.”
KRAB zinc finger proteins (2017, background): “KAP1 acts as a scaffold for a silencing complex that comprises the histone methyltransferase SETDB1 (also known as ESET) (Schultz et al., 2002), the nucleosome remodeling and deacetylation (NuRD) complex (Schultz et al.”
Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. (2005, background): “2002) and SETDB1/ESET (Schultz et al. 2002; Yang et al. 2002) gene products were demonstrated to catalyze H3-K9 methylation.”
The SET-domain protein superfamily: protein lysine methyltransferases (2005, background): “ESET has been reported to bind the co-repressor KAP-1, which acts as a molecular scaffold, targeting ESET and HP1 to euchromatic genes silenced by KRAB-domain zinc-finger proteins [ 35 ].”
Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway (2006, background): “HP1 recruitment to chromatin is enhanced by methylation of histone H3 on K9 by a KAP-1-associated histone methyltransferase SETDB1 (ref”
Control of Embryonic Stem Cell State (2011, background): “The mechanisms involved in ESC gene regulation by Cnot3 and Trim28 are not yet well understood, but Trim28 can interact with HP1 and SetDB1 to facilitate formation of repressive chromatin (Cammas et al., 2004; Schultz et al., 2002).”
A maternal-zygotic effect gene Zfp57 maintains both maternal and paternal imprints (2008, background): “They act as potent transcriptional repressors through KRAB box-mediated interaction with KAP-1/TIF-1β co-repressor complexes (Abrink et al., 2001; Friedman et al., 1996; Schultz et al., 2002; Schultz et al., 2001).”
The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36 (2006, background): “A signiﬁcant amount of H3K9 methylation resides in heterochromatic regions 21,22 , but this modiﬁcation also regulates genes found in euchromatic regions 24,25 .”
DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, background): “4C; Schultz et al. 2001, 2002; Iyengar and Farnham 2011; Quenneville et al. 2011; Zuo et al. 2012).”