PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation.
Histone lysine methylation is dynamically regulated by lysine methyltransferases and lysine demethylases. Here we show that PHD finger protein 8 (PHF8), a protein containing a PHD finger and a Jumonji C (JmjC) domain, is associated with hypomethylated rRNA genes (rDNA). PHF8 interacts with the RNA polymerase I transcription machinery and with WD repeat-containing protein 5 (WDR5)-containing H3K4 methyltransferase complexes. PHF8 exerts a positive effect on rDNA transcription, with transcriptional activation requiring both the JmjC domain and the PHD finger. PHF8 demethylates H3K9me1/2, and its catalytic activity is stimulated by adjacent H3K4me3. A point mutation within the JmjC domain that is linked to mental retardation with cleft lip and palate (XLMR-CL/P) abolishes demethylase activity and transcriptional activation. Though further work is needed to unravel the contribution of PHF8 activity to mental retardation and cleft lip/palate, our results reveal a functional interplay between H3K4 methylation and H3K9me1/2 demethylation, linking dynamic histone methylation to rDNA transcription and neural disease.
Feng
Weijun
W
Division of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
Yonezawa
Masato
M
Ye
Jing
J
Jenuwein
Thomas
T
Grummt
Ingrid
I
D045744:Cell Line, Tumor; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D011485:Protein Binding; D012335:RNA, Ribosomal / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
D006657:Histones; D012335:RNA, Ribosomal; D014157:Transcription Factors; D056466:Histone Demethylases; C511934:PHF8 protein, human