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Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [bulk RNA-seq]

ABSTRACT: Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [bulk RNA-seq]

PROVIDER: PRJNA750433 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15278809.fastq.gz	Fastqsanger.gz
	SRR15278810.fastq.gz	Fastqsanger.gz
	SRR15278811.fastq.gz	Fastqsanger.gz
	SRR15278812.fastq.gz	Fastqsanger.gz
	SRR15278813_1.fastq.gz	Fastqsanger.gz

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Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [bulk RNA-seq]

Project description:Schizophrenia (SCZ) is a chronic, serious mental disorder with severe burden on patients’ families and society. Although over 100 genes have been linked to SCZ pathogenies, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression programs in cells of brain regions highly relevant to SCZ. By comparing single-cell RNA-seq results from wild type and Setd1a+/- mice, we found Setd1a heterozygosity causes highly diverse transcriptional adaptations across different cell types in prefrontal cortex and striatum, suggesting brain region- and cell type-specific mechanisms contribute to pathophysiology of SCZ. Interestingly, we found the Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with the H3K4me3 changes. Importantly, many of the genes dysregulated in heterozygous Setd1a mice are linked to neuron morphogenesis and synaptic function. Consistently, heterozygous Setd1a mice exhibit certain behavioral features of SCZ patients. Collectively, our study establishes Setd1a heterozygous mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific changes that potentially underlying SCZ pathogenesis.

2022-01-12 | GSE181024 | GEO

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

Project description:Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

| PRJNA750428 | ENA

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [CUT&RUN]

2022-01-12 | GSE181025 | GEO

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [single-cell RNA-seq]

2022-01-12 | GSE181021 | GEO

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [CUT&RUN]

Project description:Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [CUT&RUN]

| PRJNA750439 | ENA

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [single-cell RNA-seq]

Project description:Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis [single-cell RNA-seq]

| PRJNA750436 | ENA

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis.

Project description:Schizophrenia (SCZ) is a chronic, serious mental disorder. Although more than 200 SCZ-associated genes have been identified, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a (SET domain containing 1A) haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression in brain regions highly relevant to SCZ. Single-cell RNA sequencing revealed that Setd1a heterozygosity causes highly variable transcriptional adaptations across different cell types in prefrontal cortex (PFC) and striatum. The Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with changes in histone H3 lysine 4 trimethylation. Many of the genes dysregulated in Setd1a+/- mice are involved in neuron morphogenesis and synaptic function. Consistently, Setd1a+/- mice exhibit certain behavioral features of patients with SCZ. Collectively, our study establishes Setd1a+/- mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific dysregulation that potentially underlies SCZ pathogenesis.

| S-EPMC8896793 | biostudies-literature

Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-01-12 | GSE181027 | GEO

SETD1A Regulates Psychiatric Gene Networks Involved in Genomic Stability and Synaptic Function in Rare and Sporadic Schizophrenia [bulk RNA-seq]

Project description:Rare loss-of-function (LoF) mutations in SETD1A are associated with schizophrenia (SCZ). However, how SETD1A haploinsufficiency leads to SCZ-associated phenotypes and its relevance to patients without these rare mutations is unknown. Here, we identify SETD1A bound loci and regulated genes in human prenatal cortex and isogenic pluripotent stem cell-derived neuronal models engineered with SETD1A LoF variants, including the most common patient mutation. SETD1A preferentially binds the promoters of SCZ and Bipolar risk loci that regulate chromatin remodeling, DNA repair, and synaptic function. Additionally, SETD1A binds to DNA damage prone sites in neural progenitor cells and postmitotic neurons. SETD1A haploinsufficiency causes accelerated neurogenesis, reduced neuronal complexity, and DNA damage accumulation in postmitotic neurons that is rescued by inhibiting the H3K4me2/3 demethylase KDM5. In postmortem SCZ cortical tissue, individuals who lack SETD1A mutations exhibit reduced SETD1A expression, associated with downregulation of SETD1A-regulated genes, implicating SETD1A-H3K4me dysfunction in sporadic SCZ cases. Therefore, restoring the SETD1A-H3K4me epigenetic imbalance may benefit individuals with SETD1A haploinsufficiency as well as a broader psychiatric population without SETD1A mutations.

2025-09-15 | GSE293155 | GEO

Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice

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.

2019-10-09 | GSE123652 | GEO

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