Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function
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PROVIDER: PRJNA819985 | ENA |
REPOSITORIES: ENA
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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.
2022-05-26 | PXD032742 | Pride
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.
2022-05-02 | GSE199428 | GEO
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.
2020-12-31 | GSE137944 | GEO
Project description:Nuclear interaction studies by ChIP coupled with mass spectrometry identified the COMPASS/SETD1A complex as interaction partner of the glucocorticoid receptor (GR) in murine bone marrow-derived macrophages (BMDMs). Here, we profiled H3K4me1, H3K4me2 and H3K4me3 in wild-type and Setd1a hypermorphic (Setd1aDel/+) Raw264.7 cells after LPS and Dex+LPS stimulation by spike-in ChIP-Seq.
2020-12-31 | GSE138017 | GEO
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
Project description:MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening, showed the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region, termed the FLOS (Functional Location on SETD1A) domain, is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a Cyclin K-binding site that is required for chromosomal recruitment of Cyclin K, and for DNA repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation, and suggests that targeting SETD1A and Cyclin K complexes may represent a therapeutic opportunity for AML and potentially other cancers.
2018-02-01 | GSE108614 | GEO
Project description:Developmental diversification of cortical inhibitory interneurons
| PRJNA411832 | ENA
Project description:The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its non-catalytic FLOS domain mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal and interaction partners for the FLOS domain. Our proteomics analysis against FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Targeted inhibition of both cyclin K and BuGZ/BUB3 binding motifs on SETD1A shows synergistic anti-leukemic effects. BuGZ/BUB3 localize to SETD1A-positive promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A-target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A binding and the leukemia cell proliferation. Despite the role of BuGZ/BUB3 at mitotic phase, the cell-cycle specific SETD1A restoration study indicates the roles of SETD1A at G1/S phase of cell cycle. Discovery of this complex indicates the indispensable role of the SETD1A-BuGZ axis in cancer.
2023-07-29 | GSE159145 | GEO
Project description:The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its non-catalytic FLOS domain mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal and interaction partners for the FLOS domain. Our proteomics analysis against FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Targeted inhibition of both cyclin K and BuGZ/BUB3 binding motifs on SETD1A shows synergistic anti-leukemic effects. BuGZ/BUB3 localize to SETD1A-positive promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A-target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A binding and the leukemia cell proliferation. Despite the role of BuGZ/BUB3 at mitotic phase, the cell-cycle specific SETD1A restoration study indicates the roles of SETD1A at G1/S phase of cell cycle. Discovery of this complex indicates the indispensable role of the SETD1A-BuGZ axis in cancer.
2023-07-29 | GSE159144 | GEO
Project description:Setd1a and Setd1b loss-of-function in murine macrophages
| PRJNA573920 | ENA