Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised 
promoters. The Set1 complex is responsible for most somatic H3K4me3 and contains 
the conserved subunit CxxC finger protein 1 (Cfp1), which binds to unmethylated 
CpGs and links H3K4me3 with CpG islands (CGIs). Here we report that Cfp1 plays 
unanticipated roles in organizing genome-wide H3K4me3 in embryonic stem cells. 
Cfp1 deficiency caused two contrasting phenotypes: drastic loss of H3K4me3 at 
expressed CGI-associated genes, with minimal consequences for transcription, and 
creation of "ectopic" H3K4me3 peaks at numerous regulatory regions. DNA binding 
by Cfp1 was dispensable for targeting H3K4me3 to active genes but was required 
to prevent ectopic H3K4me3 peaks. The presence of ectopic peaks at enhancers 
often coincided with increased expression of nearby genes. This suggests that 
CpG targeting prevents "leakage" of H3K4me3 to inappropriate chromatin 
compartments. Our results demonstrate that Cfp1 is a specificity factor that 
integrates multiple signals, including promoter CpG content and gene activity, 
to regulate genome-wide patterns of H3K4me3.