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Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function

Clifton, Nicholas, Bosworth, Matthew, Haan, Niels, Rees, Elliott, Holmans, Peter, Wilkinson, Lawrence, Isles, Anthony, Collins, Mark and Hall, Jeremy 2022. Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function. Human Molecular Genetics 10.1093/hmg/ddac105

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Abstract

Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A loss-of-function may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Publisher: Oxford University Press
ISSN: 0964-6906
Date of First Compliant Deposit: 9 May 2022
Date of Acceptance: 29 April 2022
Last Modified: 02 Oct 2022 02:30
URI: https://orca.cardiff.ac.uk/id/eprint/149622

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