Growth factor signaling pathways regulate a broad spectrum of cellular processes ranging from proliferation to differentiation and tissue homeostasis. Activation of a signaling pathway ultimately leads to transcriptional changes in specific target genes. Although the molecular identities of many signaling pathway components have been revealed over the last years, there is still very little knowledge of how these components induce changes in the chromatin structure of target genes, a requirement for activation or repression of these genes. A new link is provided by an interesting paper in PNAS that demonstrates that in the context of Wnt signaling the histone methyltransferase SETD8 (PR-SET7, KMT5a, SET8) is recruited to enhancer regions of Wnt-regulated genes. SETD8 establishes H4K20 monomethylation (H4K20me1) at these regulatory regions, which is crucial for full activation of these target genes.