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

• Published in: Genes & development 2004-06, Vol.18 (11), p.1251-1262
• Main Authors: Schotta, Gunnar, Lachner, Monika, Sarma, Kavitha, Ebert, Anja, Sengupta, Roopsha, Reuter, Gunter, Reinberg, Danny, Jenuwein, Thomas
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cells, Cultured; Chromobox Protein Homolog 5; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Conserved Sequence; Drosophila; Drosophila - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Female; Fibroblasts; Gene Silencing; Genes, Suppressor; Heterochromatin - genetics; Heterochromatin - metabolism; Histone Methyltransferases; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - immunology; Histones - metabolism; Lysine - metabolism; Mammals; Methylation; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Molecular Sequence Data; Protein Methyltransferases; Protein Structure, Tertiary; Repressor Proteins - genetics; Repressor Proteins - metabolism; Research Papers; Substrate Specificity
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.300704

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.