Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly.
Epigenetic gene silencing in eukaryotes is regulated in part by lysine methylation of the core histone proteins. While histone lysine methylation is known to control gene expression through the recruitment of modification-specific effector proteins, it remains unknown whether nonhistone chromatin proteins are targets for similar modification-recognition systems. Here we show that the histone H3 methyltransferase G9a contains a conserved methylation motif with marked sequence similarity to H3 itself. As with methylation of H3 lysine 9, autocatalytic G9a methylation is necessary and sufficient to mediate in vivo interaction with the epigenetic regulator heterochromatin protein 1 (HP1), and this methyl-dependent interaction can be reversed by adjacent G9a phosphorylation. NMR analysis indicates that the HP1 chromodomain recognizes methyl-G9a through a binding mode similar to that used in recognition of methyl-H3K9, demonstrating that the chromodomain functions as a generalized methyl-lysine binding module. These data reveal histone-like modification cassettes - or "histone mimics" - as a distinct class of nonhistone methylation targets and directly extend the principles of the histone code to the regulation of nonhistone proteins.
Sampath
Srihari C
SC
Laboratory of Lymphocyte Signaling, New York, NY 10021, USA. sampasc@mail.rockefeller.edu
Marazzi
Ivan
I
Yap
Kyoko L
KL
Sampath
Srinath C
SC
Krutchinsky
Andrew N
AN
Mecklenbräuker
Ingrid
I
Viale
Agnes
A
Rudensky
Eugene
E
Zhou
Ming-Ming
MM
Chait
Brian T
BT
Tarakhovsky
Alexander
A
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D019175:DNA Methylation; D005786:Gene Expression Regulation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011496:Protein Methyltransferases
D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D046912:Multiprotein Complexes; D000090266:Chromobox Protein Homolog 5; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine