Gene body methylation suppresses intragenic transcription and permits epigenetic inheritance in a cnidarian

Abstract

Across invertebrates, DNA methylation is largely restricted to the bodies of highly and constitutively expressed genes. This pattern has led to the widespread hypothesis that gene body methylation regulates gene expression and contributes to environmental adaptation and developmental plasticity, often by analogy to its roles in vertebrate genomes. However, mechanistic evidence testing these ideas remains scarce, limiting the interpretation of epigenetic variation in evolutionary and ecological contexts. Here, using the cnidarian model Nematostella vectensis, an early-branching animal which retains an ancestral methylation pattern, we show that loss of DNA methylation produces viable embryos with minimal effects on gene expression. Instead, methylation depletion causes widespread chromatin opening and spurious transcription initiation, particularly from transposable elements embedded within gene bodies. We further demonstrate that methylation is selectively restored in the germline, guided by transcription-associated chromatin, but is not globally reprogrammed after fertilization. As a result, aberrant methylation states can be inherited across generations. These findings identify gene body methylation as an evolutionarily conserved genome defence mechanism, clarify its ancestral function in animal genomes and reveal how incomplete epigenetic resetting can generate heritable regulatory variation with potential evolutionary consequences.