A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.

By Gunnar Schotta, M. Lachner, K. Sarma, Anja Ebert, Roopsha Sengupta, G. Reuter, D. Reinberg, T. Jenuwein. Genes & Development, 2004

1,176 citations recorded by the source corpus.

Histone lysine methylation is a central modification to mark functionally distinct chromatin regions. In particular, H3-K9 trimethylation has emerged as a hallmark of pericentric heterochromatin in mammals. Here we show that H4-K20 trimethylation is also focally enriched at pericentric heterochromatin. Intriguingly, H3-K9 trimethylation by the Suv39h HMTases is required for the induction of H4-K20 trimethylation, although the H4 Lys 20 position is not an intrinsic substrate for these enzymes. By using a candidate approach, we identified Suv4-20h1 and Suv4-20h2 as two novel SET domain HMTases that localize to pericentric heterochromatin and specifically act as nucleosomal H4-K20 trimethylating enzymes. Interaction of the Suv4-20h enzymes with HP1 isoforms suggests a sequential mechanism to establish H3-K9 and H4-K20 trimethylation at pericentric heterochromatin. Heterochromatic H4-K20 trimethylation is evolutionarily conserved, and in Drosophila, the Suv4-20 homolog is a novel PEV modifier to regulate position-effect variegation. Together, our data indicate a function for H4-K20 trimethylation in gene silencing and further suggest H3-K9 and H4-K20 trimethylation as important components of a repressive pathway that can index pericentric heterochromatin.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d318b033156682625c0814d8c7ad325fb71c072e

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In Molecular Biology

1. Manel Esteller
2. Yi Zhang
3. D. Reinberg
4. S. Baylin
5. Yang Shi
6. Peter A. Jones
7. Keji Zhao
8. Kairong Cui

Citations in the corpus

• The profile of repeat‐associated histone lysine methylation states in the mouse epigenome (2005, background): “The enzymes for H3-K9 and H4-K20 trimethylation at pericentric heterochromatin are known and were shown to be linked in a silencing pathway, where the activity of the Suv39h enzymes precedes nucleosomal methylation by the Suv4-20h HMTases (Schotta et al, 2004).”
• The SET-domain protein superfamily: protein lysine methyltransferases (2005, background): “H4 K20 Cell cycle-dependent silencing, mitosis and cytokinesis [52,53] Hs and Dm SET8 Heterochromatic silencing Dm, Mm, and Hs SUV4-20H1 and SUV4-20H2 [48] Transcriptional regulation Mm NSD1 Transcriptional activation (in conjunction with ASH1-mediated Dm ASH1 methylation of H3 K4 and H3 K9) Recruit”
• Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer (2005, background): “Trimethylation of H4-Lys20 is a marker of constitutive heterochromati”
• JmjC-domain-containing proteins and histone demethylation (2006, background): “Enzymes that contain SET domains, much like JmjC-domain proteins, fall into defined protein families, some of which have redundant modification-site specificit”
• ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. (2008, positive): “Consistent with previous work, the densely staining DAPI regions were enriched for K9 trimethylated histone H3 and the centromeric protein CENP-A, markers of heterochromatinization (Guenatri et al., 2004; Schotta et al., 2004), while the intervening euchromatin was unstained (Figures 2A and 2B).”
• Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. (2006, background): “Trimethylation at H3-K9 and H4-K20 has been shown to be associated with constitutive heterochromatin (Schotta et al., 2004b), while H3-K9Me2 and K9Me3, along with H3-K27Me3 have been associated with X inactivation (Bean et al., 2004; Cowell et al., 2002; Kelly et al., 2002; Reuben and Lin, 2002;…”
• Regulation of histone methylation by demethylimination and demethylation (2007, background): “Defined H4K20 methylation states demarcate different genomic regions, with H4K40me3 found in constitutive heterochromatin 107,108 and H4K20me2 or H4K20me1 occurring in a non-overlapping fashion throughout euchromatic reg ions 109 .”
• A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing (2007, background): “Thus, trimethylated H3K9, which is characteristic of silenced transcription in pericentromeric region”
• High-resolution profiling of histone methylations in the human genome. (2007, background): “H4K20me3 is associated with heterochromatin, while H4K20me1 is enriched in promoter or coding regions of active genes (Schotta et al., 2004; Talasz et al., 2005; Vakoc et al., 2006).”
• Telomere length, stem cells and aging. (2007, background): “These histone marks include trimethylation of H3K9 and H4K20 by the histone methyltransferases suppressor of variegation 3-9 homologs (Suv39h1 and h2) and suppressor of variegation 4-20 homologs (Suv4-20h1 and h2), respectivel”
• The diverse functions of histone lysine methylation (2005, background): “Interestingly, Suv4–20h1/Suv4–20h2 and specific HP1 isoforms are capable of directly interacting with one another, and H4-K20 methylation is abolished at pericentric regions in the absence of Suv3–9h1/Suv3–9h2 function 50 .”
• The hallmarks of aging. (2013, background): “In particular, heterochromatin assembly at pericentric regions requires trimethylation of histones H3K9 and H4K20, as well as HP1a binding, and is important for chromosomal stability (Schotta et al., 2004).”