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

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

PROVIDER: PRJNA819985 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18485900_1.fastq.gz	Fastqsanger.gz
	SRR18485900_2.fastq.gz	Fastqsanger.gz
	SRR18485901_1.fastq.gz	Fastqsanger.gz
	SRR18485901_2.fastq.gz	Fastqsanger.gz
	SRR18485902_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

Project 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.

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Project description:SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.

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Project description:Setd1bKO primary murine bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide (LPS) or dexamethasone and LPS (Dex+LPS) and gene expression differences in response to treatment analysed by PolyA RNA-Sequencing. No Dex-treatment dependent gene expression differences were identified. Setd1aDel/+ Raw264.7 cells with reduced Setd1a expression were analyzed with regards to their reponse to Dex when inflammatorily challenged with LPS by mRNA-Seq. We observed reduced GR-dependent gene acivation in Setd1a hypermorphic Raw264.7 cells. Wild type and Setd1aDel/+ Raw264.7 cells were treated with LPS or LPS and interferon beta (IFNB1) to show the IFNB1-dependent loss of gene expression in LPS-stimulated Setd1aDel/+ cells.

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SETD1A protects from senescence through regulation of the mitotic gene expression program

Project description:SETD1A, a member of the Set1/COMPASS family maintaining H3K4 methylation in the promoters of transcriptionally active genes, is critical for the execution of developmental gene expression and is overexpressed in multiple cancers including breast cancer1-3. Here we show that SETD1A is essential for supporting cellular mitotic processes and consequentially, its depletion leads to senescence. SETD1A directly regulates the expression of several genes orchestrating mitosis and DNA damage responses and its depletion results in multiple mitotic defects including chromosome misalignment and segregation defects. Senescence-associated cell cycle arrest in SETD1A knockdown cells is independent of the mutational status of p53, RB and p16, key mediators of this process, instead, is sustained through direct transcriptional suppression of SKP2, the ubiquitin ligase, which degrades p27 and p21. Rare cells escape senescence and re-enter the cell cycle by restoring SKP2 expression but with enhanced genomic instability. In >200 cancer cell lines and in primary circulating tumor cells, expression of SETD1A correlates with genes involved in mitosis and cell cycle suggesting a role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A encodes a chromatin modifier, whose modulation may maintain the balance between senescence and genomic instability in cells.

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