WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.
Histone H3 lysine 4 (K4) methylation has been linked to the transcriptional activation in a variety of eukaryotic species. Here we show that a common component of MLL1, MLL2, and hSet1 H3 K4 methyltransferase complexes, the WD40-repeat protein WDR5, directly associates with histone H3 di- and trimethylated at K4 and with H3-K4-dimethylated nucleosomes. WDR5 is required for binding of the methyltransferase complex to the K4-dimethylated H3 tail as well as for global H3 K4 trimethylation and HOX gene activation in human cells. WDR5 is essential for vertebrate development, in that WDR5-depleted X. laevis tadpoles exhibit a variety of developmental defects and abnormal spatial Hox gene expression. Our results are the first demonstration that a WD40-repeat protein acts as a module for recognition of a specific histone modification and suggest a mechanism for reading and writing an epigenetic mark for gene activation.
Wysocka
Joanna
J
Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10021, USA.
Swigut
Tomek
T
Milne
Thomas A
TA
Dou
Yali
Y
Zhang
Xin
X
Burlingame
Alma L
AL
Roeder
Robert G
RG
Brivanlou
Ali H
AH
Allis
C David
CD
D000818:Animals; D002460:Cell Line; D005801:Genes, Homeobox / Q000235:genetics / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D008745:Methylation; D008840:Microfilament Proteins / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D014714:Vertebrates / Q000196:embryology*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000502:physiology
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008840:Microfilament Proteins; D009707:Nucleosomes; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase; D020962:Heterotrimeric GTP-Binding Proteins; D008239:Lysine