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

Abstract

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 tRNA wobble 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.

Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia

“…Recently, Elp1 has been shown to regulate neuronal gene expression in a dose-dependent manner in a humanized mouse model of FD ( Morini et al, 2021 ). Importantly, these functions of Elp1 could be direct or indirect via its essential role as part of the elongator complex in modifying tRNAs during translation ( Cameron et al, 2021 ; Chen et al, 2009b ; Chen et al, 2009a ; Goffena et al, 2018 ; Huang et al, 2005 ; Huang et al, 2008 ; Karlsborn et al, 2014 ; Karlsborn et al, 2015 ). Indeed, the dorsal root ganglia proteome in Elp1 CKO exhibits substantial changes (compared to Control) across a wide range of cellular functions, including axon guidance and pathfinding ( Goffena et al, 2018 ).…”

“…Elp1 is a requisite scaffolding protein of the six-subunit elongator complex that regulates translation by modifying particular tRNAs ( Huang et al, 2005 ; Huang et al, 2008 ; Karlsborn et al, 2014 ; Xu et al, 2015 ; Esberg et al, 2006 ). Deletion of elongator subunits has been shown to alter tRNA modifications and protein expression in several systems ( Cameron et al, 2021 ; Chen et al, 2009b ; Esberg et al, 2006 ; Goffena et al, 2018 ; Karlsborn et al, 2014 ; Kojic et al, 2021 ). Consequently, loss or reduction of Elp1 protein leads directly or indirectly to the clinical phenotypes seen in FD, which include impaired pain and temperature sensation, feeding and swallowing difficulties, blood pressure instability, tachycardia, optic neuropathy, and gastrointestinal dysfunction, among other symptoms.…”