PXD032742

PXD032742 is an original dataset announced via ProteomeXchange.

Title	Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-05-26
AnnouncementXML	Submission_2022-05-26_05:35:18.843.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mark Collins
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-23 07:30:30	ID requested
⏵ 1	2022-05-26 05:35:19	announced

Clifton NE, Bosworth ML, Haan N, Rees E, Holmans PA, Wilkinson LS, Isles AR, Collins MO, Hall J, Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function. Hum Mol Genet, 31(18):3095-3106(2022) [pubmed]

submitter keyword: SETD1A, Schizophrenia, Development, Neuronal, Synaptosome

Mark Collins
contact affiliation	School of Biosciences University of Sheffield Sheffield, S10 2TN United Kingdom
contact email	mark.collins@sheffield.ac.uk
lab head
Mark Collins
contact affiliation	University of Sheffield
contact email	mark.collins@sheffield.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032742
     1. Label: PRIDE project
     2. Name: Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function