Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Elisabetta Morini; Dadi Gao; Emily M Logan; Monica Salani; Aram J Krauson; Anil Chekuri; Yei-Tsung Chen; Ashok Ragavendran; Probir Chakravarty; Serkan Erdin; Alexei Stortchevoi; Jesper Q Svejstrup; Michael E Talkowski; Susan A Slaugenhaupt

doi:10.1016/j.jgg.2021.11.011

Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

J Genet Genomics. 2022 Jul;49(7):654-665. doi: 10.1016/j.jgg.2021.11.011. Epub 2021 Dec 9.

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
² Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
⁴ Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taiwan.
⁵ Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
⁷ Mechanisms of Transcription Laboratory, The Francis Crick Institute, London, UK; Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
⁸ Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. Electronic address: slaugenhaupt@mgh.harvard.edu.

Abstract

Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1^-/-) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.

Keywords: ELP1; Elongator; Familial dysautonomia; Neurodevelopmental disease; Transcriptional elongation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Carrier Proteins* / genetics
Disease Models, Animal
Dysautonomia, Familial* / genetics
Dysautonomia, Familial* / metabolism
Gene Expression
Homozygote
Humans
Mice
Sequence Deletion

Substances

Carrier Proteins

Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding