Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BRD4 in schizophrenia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144639 | GEO | 2022/01/12
REPOSITORIES: GEO
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Project description:Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we apply an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observe hyper-acetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrate that the bromodomain and extraterminal (BET) protein, BRD4, is a bona fide ‘reader’ of H2A.Z acetylation, and further provide evidence that BET family protein inhibition ameliorates transcriptional abnormalities in patient-derived neurons. Thus, treatments aimed at alleviating BET protein interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.
2022-05-06 | PXD031767 | Pride
Project description:The histone variant H2A.Z plays key roles in gene expression, DNA repair, and centromere function. H2A.Z deposition is controlled by SWR-C chromatin remodeling enzymes that catalyze the nucleosomal exchange of canonical H2A with H2A.Z. Here we report that acetylation of histone H3 lysine 56 (H3-K56Ac) alters the substrate specificity of SWR-C, leading to promiscuous dimer exchange where either H2A.Z or H2A can be exchanged from nucleosomes. This result is confirmed in vivo, where genome-wide analysis demonstrates widespread decreases in H2A.Z levels in yeast mutants with hyperacetylated H3K56. Our work also suggests that a conserved SWR-C subunit may function as a M-bM-^@M-^\lockM-bM-^@M-^] that prevents removal of H2A.Z from nucleosomes. Our study identifies a histone modification that regulates a chromatin remodeling reaction and provides insights into how histone variants and nucleosome turnover can be controlled by chromatin regulators. H2A.Z ChIP seq experiments in mutants with constitutive H3K56ac
2013-04-15 | E-GEOD-43935 | biostudies-arrayexpress
Project description:Creating long-lasting memories relies on learning-induced changes in gene expression, which are regulated by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histone proteins are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies began to investigate histone variants as key regulators of memory formation, PTMs are rarely considered in relation to their function. Here, we analyze the role of acetylation of histone variant H2A.Z.1 in memory and gene expression. To this end, we developed AAV constructs to overexpress mutated H2A.Z.1 isoforms that either mimic acetylation (acetyl-mimetic) by replacing lysines 4, 7 and 11 with glutamine (KQ), or that have impaired acetylation (acetyl-defective) by replacing the same lysine with alanine (KA). We found that overexpression of the acetyl-mimetic (H2A.Z.1KQ) or the acetyl-defective (H2A.Z.1KA) isoforms of H2A.Z.1 in the hippocampus produces different effects on memory depending on strength of the task and sex, with H2A.Z.1KQ generally having a beneficial effect on memory, while H2A.Z.1KA results in impaired memory. We further analyzed gene expression data and found that H2A.Z.1KQ and H2A.Z.1KA uniquely impact the expression of different classes of genes in females and males. However, different genes are regulated by different isoforms in the 2 sexes. Finally, we describe, for the first time, that H2A.Z is involved in the alternative splicing of neuronal genes. Notably, H2A.Z depletion and its replacement with different isoforms influence transcription and splicing of different genes, suggesting that H2A.Z.1 can regulate genes through splicing and expression levels. This is the first study demonstrating that direct manipulation of the levels of AcH2A.Z regulates memory, gene expression and splicing. Overall, this study adds another layer of complexity to the contribution of histone variants to higher brain functions, consolidating H2A.Z as a key regulator of memory.
2024-03-05 | GSE260704 | GEO
Project description:Creating long-lasting memories relies on learning-induced changes in gene expression, which are regulated by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histone proteins are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies began to investigate histone variants as key regulators of memory formation, PTMs are rarely considered in relation to their function. Here, we analyze the role of acetylation of histone variant H2A.Z.1 in memory and gene expression. To this end, we developed AAV constructs to overexpress mutated H2A.Z.1 isoforms that either mimic acetylation (acetyl-mimetic) by replacing lysines 4, 7 and 11 with glutamine (KQ), or that have impaired acetylation (acetyl-defective) by replacing the same lysine with alanine (KA). We found that overexpression of the acetyl-mimetic (H2A.Z.1KQ) or the acetyl-defective (H2A.Z.1KA) isoforms of H2A.Z.1 in the hippocampus produces different effects on memory depending on strength of the task and sex, with H2A.Z.1KQ generally having a beneficial effect on memory, while H2A.Z.1KA results in impaired memory. We further analyzed gene expression data and found that H2A.Z.1KQ and H2A.Z.1KA uniquely impact the expression of different classes of genes in females and males. However, different genes are regulated by different isoforms in the 2 sexes. Finally, we describe, for the first time, that H2A.Z is involved in the alternative splicing of neuronal genes. Notably, H2A.Z depletion and its replacement with different isoforms influence transcription and splicing of different genes, suggesting that H2A.Z.1 can regulate genes through splicing and expression levels. This is the first study demonstrating that direct manipulation of the levels of AcH2A.Z regulates memory, gene expression and splicing. Overall, this study adds another layer of complexity to the contribution of histone variants to higher brain functions, consolidating H2A.Z as a key regulator of memory.
2024-03-01 | GSE242179 | GEO
Project description:Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating mRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain. One or two replicates of the histone modifications (H3K27me3 and H2A.z), total histone proteins (H2A.z and H3), and ATPase Chd4 using postnatal day 22 cerebella from wild type (WT) or Chd4 conditional knockout (cKO) mice were examined using libraries prepared with the Illumina ChIP-Seq DNA Sample Prep Kit. Four replicates of total RNA were extracted from postnatal day 27-28 cerebella from rotarod-trained or control homecage mice, or Chd4 cKO or WT mice using Trizol and reverse-transcribed with oligo-dT priming. Three replicates of immunoprecipitated Sync-TRAP RNA or the input control using postnatal day 12 Chd4 cKO or WT cerebella were purified and amplified with Ovation RNA-Seq System V2 (NuGEN). All samples were sequenced on the Illumina HiSeq 2000 platform.
2016-07-18 | E-GEOD-83253 | biostudies-arrayexpress
Project description:The histone variant H2A.Z plays key roles in gene expression, DNA repair, and centromere function. H2A.Z deposition is controlled by SWR-C chromatin remodeling enzymes that catalyze the nucleosomal exchange of canonical H2A with H2A.Z. Here we report that acetylation of histone H3 lysine 56 (H3-K56Ac) alters the substrate specificity of SWR-C, leading to promiscuous dimer exchange where either H2A.Z or H2A can be exchanged from nucleosomes. This result is confirmed in vivo, where genome-wide analysis demonstrates widespread decreases in H2A.Z levels in yeast mutants with hyperacetylated H3K56. Our work also suggests that a conserved SWR-C subunit may function as a “lock” that prevents removal of H2A.Z from nucleosomes. Our study identifies a histone modification that regulates a chromatin remodeling reaction and provides insights into how histone variants and nucleosome turnover can be controlled by chromatin regulators.
2013-04-15 | GSE43935 | GEO
Project description:Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating mRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain.
2016-07-18 | GSE83253 | GEO
Project description:Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients. Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subject to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p<0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples.
2013-11-01 | GSE46562 | GEO
Project description:We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ) -associated genetic factor. Several genes in the deleted region have been implicated; one of the more promising candidates is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. miRNA profiling of 7 SZ samples and 9 Control samples derived from iPSCs
2015-08-01 | E-GEOD-65367 | biostudies-arrayexpress
Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the “age” of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus. We directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into forebrain neurons. SZ hiPSC differentiated into forebrain neurons have altered expression of a number of synaptic genes. Methods: We compared global transcription of forebrain neurons from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC neuron samples; 107 genes were significantly differentially expressed (FDR<0.01)
2016-04-21 | GSE63734 | GEO