A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.
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.
Schotta
Gunnar
G
Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, A-1030 Vienna, Austria.
Lachner
Monika
M
Sarma
Kavitha
K
Ebert
Anja
A
Sengupta
Roopsha
R
Reuter
Gunter
G
Reinberg
Danny
D
Jenuwein
Thomas
T
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D020868:Gene Silencing; D016153:Genes, Suppressor; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000276:immunology / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008322:Mammals; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D006570:Heterochromatin; D006657:Histones; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C498700:Suv39h1 protein, mouse; D000076983:Histone Methyltransferases; C487546:Hmt4-20 protein, Drosophila; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine