The evolution of the first body axis in the animal kingdom and an extensive ability to regenerate makes Hydra, a Cnidarian, an excellent model system to understand the underlying epigenetic mechanisms. We identify that SETD8 is critical for regeneration, and H4K20me1 colocalizes with transcriptional activation machinery locally at the ß-catenin bound TCF/LEF binding sites on the promoters of head-associated genes, marking an epigenetic activation node. Contrastingly, a global genome-wide analysis of the H4K20me1 occupancy revealed a negative correlation with transcriptional activation. We propose H4K20me1 as a general repressive histone mark in Cnidaria and describe its dichotomous role in transcriptional regulation in Hydra. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for the histone modification H4K20me1 in control and ALP treated Hydra polyps.