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

• Published in: Molecular cell Vol. 26; no. 1; pp. 103 - 115
• Main Authors: Rudolph, Thomas, Yonezawa, Masato, Lein, Sandro, Heidrich, Kathleen, Kubicek, Stefan, Schäfer, Christiane, Phalke, Sameer, Walther, Matthias, Schmidt, Andreas, Jenuwein, Thomas, Reuter, Gunter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.04.2007
• Subjects: Animals; DNA; DNA Methylation; Drosophila melanogaster - embryology; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Euchromatin - metabolism; Female; Gene Expression Regulation, Developmental; Gene Silencing; Heterochromatin - metabolism; Histone Demethylases; Histones - genetics; Histones - metabolism; Methyltransferases - genetics; Models, Biological; Molecular Structure; Oxidoreductases, N-Demethylating - genetics; Oxidoreductases, N-Demethylating - metabolism; DNA
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2007.02.025

Epigenetic indexing of chromatin domains by histone lysine methylation requires the balanced coordination of methyltransferase and demethylase activities. Here, we show that SU(VAR)3-3, the Drosophila homolog of the human LSD1 amine oxidase, demethylates H3K4me2 and H3K4me1 and facilitates subsequent H3K9 methylation by SU(VAR)3-9. Su(var)3-3 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 Su(var)3-3/+ 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.