Loss of Elp1 perturbs histone H2A.Z and the Notch signaling pathway

Elongator dysfunction is increasingly recognized as a contributor to multiple neurodevelopmental and neurodegenerative disorders including familial dysautonomia, intellectual disability, amyotrophic lateral sclerosis, and autism spectrum disorder. Although numerous cellular processes are perturbed in the context of Elongator loss, converging evidence from multiple studies has resolved Elongator's primary function in the cell to the modification of tRNAwobble uridines and the translational regulation of codon-biased genes. Here we characterize H2a.z, encoding the variant H2a histone H2A.Z, as an indirect Elongator target. We further show that canonical Notch signaling, a pathway directed by H2A.Z, is perturbed as a consequence of Elp1 loss. Finally, we demonstrate that hyperacetylation of H2A.Z and other histones via exposure to the histone deacetylase inhibitor Trichostatin A during neurogenesis corrects the expression of Notch3 and rescues the development of sensory neurons in embryos lacking the Elp1 Elongator subunit.

Automated summary

Elongator dysfunction is linked to various neurodevelopmental and neurodegenerative disorders, mainly through the modification of tRNA and translational regulation of specific genes. H2a.z is identified as an indirect target of Elongator, affecting Notch signaling. Using histone deacetylase inhibitor during neurogenesis can correct gene expression and rescue neuron development in Elongator-deficient embryos.