Loss of Elp1 perturbs histone H2A.Z and the Notch signaling pathway
BreAnna Cameron,
Elin Lehrmann,
Tien Chih,
Joseph Walters,
Richard Buksch,
Sara Snyder,
Joy Goffena,
Frances Lefcort,
Kevin G. Becker,
Lynn George
Affiliations
BreAnna Cameron
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
Elin Lehrmann
Computational Biology & Genomics Core (CBGC), Laboratory of Genetics and Genomics (LGG), Department of Health and Human Services (DHHS), National Institute on Aging, Intramural Research Program (NIA IRP), National Institutes of Health (NIH), Biomedical Research Center, Baltimore, MD 21224, USA
Tien Chih
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
Joseph Walters
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
Richard Buksch
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
Sara Snyder
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
Joy Goffena
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
Frances Lefcort
Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA
Kevin G. Becker
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Lynn George
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA
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.
