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EZH2-mediated H3K27me3 targets transcriptional circuits of neuronal differentiation ChIP-seq

ABSTRACT: Our work describes novel roles for EZH2 in the specification of cortical neurons. Previous reports established the current model of EZH2-mediated control of neuronal progenitors differentiation through the regulation of their proliferation and developmental transitions. We built on these findings and studied the role of EZH2 in post-mitotic glutamatergic neurons differentiated from embryonic stem cells, a particularly relevant cell type where the impact of its regulation has thus far remained elusive. Briefly, our key results can be summarized as follows: 1. The conditional deletion of EZH2 at the moment of cell cycle exit in neural progenitors allowed us to study the role of EZH2 selectively in post-mitotic glutamatergic neurons. 2. Time course transcriptomic and epigenomic analyses of H3K27me3 in absence of EZH2 revealed a significant dysregulation of transcriptional networks affecting synaptic plasticity, in particular long term depression. 3. These analyses also revealed potential novel roles of EZH2 in controlling the regulation between the glutamatergic signature and the GABAergic one, suggesting a mechanism entailing failure of Prdm13 repression, a histone methyltransferase with a known role in determining GABAergic neurons specification.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Mus musculus

SUBMITTER: Serena Buontempo

PROVIDER: E-MTAB-11363 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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EZH2-mediated H3K27me3 targets transcriptional circuits of neuronal differentiation

Project description:Our work describes novel roles for EZH2 in the specification of cortical neurons. Previous reports established the current model of EZH2-mediated control of neuronal progenitors differentiation through the regulation of their proliferation and developmental transitions. We built on these findings and studied the role of EZH2 in post-mitotic glutamatergic neurons differentiated from embryonic stem cells, a particularly relevant cell type where the impact of its regulation has thus far remained elusive. Briefly, our key results can be summarized as follows: 1. The conditional deletion of EZH2 at the moment of cell cycle exit in neural progenitors allowed us to study the role of EZH2 selectively in post-mitotic glutamatergic neurons. 2. Time course transcriptomic and epigenomic analyses of H3K27me3 in absence of EZH2 revealed a significant dysregulation of transcriptional networks affecting synaptic plasticity, in particular long term depression. 3. These analyses also revealed potential novel roles of EZH2 in controlling the regulation between the glutamatergic signature and the GABAergic one, suggesting a mechanism entailing failure of Prdm13 repression, a histone methyltransferase with a known role in determining GABAergic neurons specification.

2022-04-18 | E-MTAB-11387 | biostudies-arrayexpress

Cell-type based analysis of microRNA profiles in the mouse brain

Project description:MicroRNAs (miRNA) are implicated in brain development and function but the underlying mechanisms have been difficult to study in part due to cellular heterogeneity in neural circuits. To systematically analyze miRNA expression in neurons, we have established a miRNA tagging and affinity purification (miRAP) method that is targeted to cell types through the Cre-loxP binary system in mice. Our studies of the neocortex and cerebellum reveal the expression of a large fraction of known miRNAs with distinct profiles in glutamatergic and GABAergic neurons, and subtypes of GABAergic neurons. We further detected putative novel miRNAs, tissue or cell type-specific strand selection of miRNAs, and miRNA editing. Our method thus will facilitate a systematic analysis of miRNA expression and regulation in specific neuron types in the context of neuronal development, physiology, plasticity, pathology and disease models, and is generally applicable to other cell types and tissues. RNA was extracted from miRNA tagging samples(Ago2 IP or Myc IP), processed and sequenced on Illumina genome analyzer

2011-06-29 | E-GEOD-30286 | biostudies-arrayexpress

Gephyrin interacts with the K-Cl co-transporter KCC2 to regulate its surface expression and function in cortical neurons

Project description:The K+-Cl- co-transporter KCC2, encoded by the Slc12a5 gene, is a neuron-specific chloride extruder that tunes the strength and polarity of GABAA receptor-mediated transmission. Besides its canonical ion-transport function, KCC2 also regulates spinogenesis and excitatory synaptic function through interaction with a variety of molecular partners. KCC2 is enriched in the vicinity of both glutamatergic and GABAergic synapses, the activity of which in turn regulates its membrane stability and function. KCC2 interaction with submembrane actin cytoskeleton via 4.1N is known to control its anchoring in the vicinity of glutamatergic synapses on dendritic spines. However, the molecular determinants of KCC2 clustering near GABAergic synapses remain unknown. Here, we use proteomics to identify novel KCC2 interacting proteins in adult rat cortex. We identify both known and novel candidate KCC2 partners, including some involved in neuronal development and synaptic transmission. These include gephyrin, the main scaffolding molecule at GABAergic synapses. Gephyrin interaction with endogenous KCC2 was confirmed by immunoprecipitation from rat brain extracts. We show that gephyrin stabilizes plasmalemmal KCC2 and promotes its clustering, notably but not exclusively near GABAergic synapses, thereby controlling KCC2-mediated chloride extrusion. This study identifies gephyrin as a novel KCC2 anchoring molecule that regulates its membrane expression and function in cortical neurons.

2021-11-29 | PXD022412 | Pride

Mutation of a schizophrenia risk gene SETD1A alters neuronal network activity in human neurons through cAMP/PKA pathway

Project description:Using CRISPR/Cas9 to generate an hiPSC line with SETD1A haploinsufficiency and differentiating it into glutamatergic and GABAergic neurons, we found that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was predominantly defined by increased network burst frequency, whereas unchanged global firing activity. In individual neurons, this network phenotype was reflected functionally by increased synchronized synaptic inputs and structurally by increased somatodendritic complexity in both glutamatergic and GABAergic neurons. The transcriptome profile in SETD1A haploinsufficient neurons demonstrated perturbations in gene sets associated with schizophrenia, synaptic transmission, and glutamatergic synaptic function. In addition, transcriptomic data suggested cAMP/PKA pathway might be disturbed in SETD1A haploinsufficient networks, which was further verified by pharmacological experiments.

2021-07-23 | GSE180648 | GEO

Aberrant Neuronal Connectivity and Network Activity of Neurons Derived from Patients with Idiopathic Schizophrenia

Project description:Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. Patch-clamp analyses revealed differential processing of excitatory input with markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons and decreased spontaneous EPSC from glutamatergic SCZ neurons. Likewise, we observed decreased amplitudes of calcium signals selectively in GABAergic neurons while frequency was increased in both neuronal populations. Finally, MEA recordings from neuronal networks indicate increased synchronization of network activity. In conclusion, our results suggest selective deregulation of neuronal activity and synaptic transmission in SCZ samples, providing evidence for differential signal processing in GABAergic and glutamatergic neurons as a potential base for aberrant network synchronization.

2024-11-25 | GSE282524 | GEO

Distinct mechanisms of non-autonomous UPRER mediated by GABAergic, glutamatergic, and octopaminergic neurons

Project description:The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic and dopaminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while minor, but statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

2024-06-15 | E-MTAB-14132 | biostudies-arrayexpress

Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition

Project description:Diversification of cell adhesion molecules by alternative splicing is proposed to underlie molecular codes for neuronal wiring. Transcriptomic approaches mapped detailed cell type-specific mRNA splicing programs. However, it has been hard to probe synapse-specific localization and function of the resulting protein splice isoforms, or “proteoforms”, in vivo. We here apply a proteoform-centric workflow in mice to test synapse-specific functions of splice isoforms of the synaptic adhesion molecule Neurexin-3 (NRXN3). We uncover a major proteoform, NRXN3 AS5, that is highly expressed in GABAergic interneurons and dendrite-targeting GABAergic terminals. NRXN3 AS5 abundance significantly diverges from the distribution of the Nrxn3 mRNA and is gated by translation-repressive elements. Nrxn3 AS5 isoform deletion results in selective impairment of dendrite-targeting interneuron synapses in the dentate gyrus without affecting somatic inhibition or glutamatergic perforant-path synapses. This work establishes cell- and synapse-specific functions of a specific neurexin proteoform and highlights the importance of alternative splicing regulation for synapse specification.

2022-02-11 | PXD031379 | Pride

Allele-specific open chromatin in human neurons elucidates functional noncoding disease variants

Project description:ASoC variants are prevalent and cell type-specific ASoC variants were over-represented in intergenic regions and active enhancers. The collection includes ATAC-Seq and RNA-Seq data that were taken from human iPS cells and their derived neuronal cells (neural progenitor cells, cortical glutamatergic neurons, GABAergic neurons, and dopaminergic neurons).

2020-05-05 | GSE129017 | GEO

Single-nucleus transcriptional profiling of Gad2-positive neurons from the mouse lateral habenula with distinct expression of neurotransmitter-related genes

Project description:Glutamatergic projection neurons of the lateral habenula (LHb) effect behavioral statemodulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that control LHb output is of interest for understanding motivated behaviors. A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic synthesizing enzyme GAD2 and are capable of inhibiting nearby LHb projection neurons. However, these neurons lack most markers of classic inhibitory interneurons, and they co-express the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting followed by single nuclear RNA sequencing (FANS-snRNAseq) to determine the full transcriptional profile of GAD2+ neurons isolated from LHb. Our data demonstrate that LHb GAD2+ neurons co-express markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from GABAergic interneurons or habenular glutamatergic neurons. We show sex-specific differences in gene expression in this neuronal population and find that these gene sets are enriched for genes involved in depression. Finally, we identify the Ntng2 gene encoding the cell adhesion protein Netrin-G2 as a selective marker of LHb GAD2+ neurons that may contribute to their target projections. These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of neurons in the LHb.

2022-11-08 | GSE179198 | GEO

PRO-seq in control and H3.3 K4A mutant mESCs

Project description:Study to investigate the role of histone residues H3K4 and H3K36 for gene expression, histone localization and neuronal lineage specification by mutation of K4 and K36 in H3.3 to alanine. Histone variant H3.3 differs from the canonical H3.1/H3.2 by only 4 to 5 amino acids, which are necessary for nucleosome assembly independent of DNA replication, and is encoded by two gene copies. Complete loss of the two H3.3 genes (H3f3a and H3f3b) leads to embryonic lethality while single gene knockout yields viable mice. We used CRISPR-Cas9 to delete H3f3a and introduce homozygous point-mutations into H3f3b, thus ensuring that the entire pool of H3.3 protein carries the mutation of interest. We differentiated H3.3ctrl (H3f3a knock-out; H3f3b wild type), H3.3K4A mutant (H3f3a knock-out; H3f3b K4A) and H3.3K36A mutant (H3f3a knock-out; H3f3b K36A) ESCs into glutamatergic neurons. To assess the effect of the K4A mutation on Pol II activity, nascent RNA levels were mesaured by PRO-seq.

2020-01-28 | E-MTAB-8617 | biostudies-arrayexpress

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