Heterochromatin Formation in Drosophila Is Initiated through Active Removal of H3K4 Methylation by the LSD1 Homolog SU(VAR)3-3

Molecular Cell, Volume 26, Issue 1, 13 April 2007, Pages 103-115
Thomas Rudolph, Masato Yonezawa, Sandro Lein, Kathleen Heidrich, Stefan Kubicek, Christiane Schäfer, Sameer Phalke, Matthias Walther, Andreas Schmidt, Thomas Jenuwein and Gunter Reuter

Summary

Epigenetic indexing of chromatin domains byhistone lysine methylation requires the balanced coordination of methyltransferase and demethylase activities. Here, we show that SU(VAR)3-3, the homolog of the human LSD1 amine oxidase, demethylates H3K4me2 and H3K4me1 and facilitates subsequent H3K9 methylation by SU(VAR)3-9. mutations suppress heterochromatic gene silencing, display elevated levels of H3K4me2, and prevent extension of H3K9me2 at pericentric heterochromatin. SU(VAR)3-3 colocalizes with H3K4me2 in interband regions and is abundant during embryogenesis and in syncytial blastoderm, where it appears concentrated at prospective heterochromatin during cycle 14. In embryos of / females, H3K4me2 accumulates in primordial germ cells, and the deregulated expansion of H3K4me2 antagonizes heterochromatic H3K9me2 in blastoderm cells. Our data indicate an early developmental function for the SU(VAR)3-3 demethylase in controlling euchromatic and heterochromatic domains and reveal a hierarchy in which SU(VAR)3-3-mediated removal of activating histone marks is a prerequisite for subsequent heterochromatin formation by H3K9 methylation.