Inter and transgenerational impact of H3K4 methylation in neuronal homeostasis.

Epigenetic marks and associated traits can be transmitted for one or more generations, phenomena known respectively as inter- or transgenerational epigenetic inheritance. It remains unknown if genetically and conditionally induced aberrant epigenetic states can influence the development of the nervous system across generations. Here, we show, using Caenorhabditis elegans as a model system, that alteration of H3K4me3 levels in the parental generation, caused by genetic manipulation or changes in parental conditions, has, respectively, trans- and intergenerational effects on H3K4 methylome, transcriptome, and nervous system development. Thus, our study reveals the relevance of H3K4me3 transmission and maintenance in preventing long-lasting deleterious effects in nervous system homeostasis.

Regulators of H3K4 methylation mutated in neurodevelopmental disorders control axon guidance in Caenorhabditis elegans.

Post-translational histone modifications regulate chromatin compaction and gene expression to control many aspects of development. Mutations in genes encoding regulators of H3K4 methylation are causally associated with neurodevelopmental disorders characterized by intellectual disability and deficits in motor functions. However, it remains unclear how H3K4 methylation influences nervous system development and contributes to the aetiology of disease. Here, we show that the catalytic activity of set-2, the Caenorhabditis elegans homologue of the H3K4 methyltransferase KMT2F/G (SETD1A/B) genes, controls embryonic transcription of neuronal genes and is required for establishing proper axon guidance, and for neuronal functions related to locomotion and learning. Moreover, we uncover a striking correlation between components of the H3K4 regulatory machinery mutated in neurodevelopmental disorders and the process of axon guidance in C. elegans Thus, our study supports an epigenetic-based model for the aetiology of neurodevelopmental disorders, based on an aberrant axon guidance process originating from deregulated H3K4 methylation.