A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin (original) (raw)

  1. Gunnar Schotta1,4,
  2. Monika Lachner1,4,
  3. Kavitha Sarma2,
  4. Anja Ebert3,
  5. Roopsha Sengupta1,
  6. Gunter Reuter3,
  7. Danny Reinberg2, and
  8. Thomas Jenuwein1,5
  9. 1Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, A-1030 Vienna, Austria; 2Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA; 3Martin-Luther University Halle-Wittenberg, Biologicum, 06120 Halle, Germany

Abstract

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.

Footnotes