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PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE189018 | GEO | 2022/07/11

REPOSITORIES: GEO

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PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons.

Project description:How neurons can maintain cellular identity over an entire life span remains largely unknown. Here, we show that maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2 component, Eed, in these neurons resulted in global loss of H3K27me3, followed by a gradual activation of genes harboring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was lost at these PRC2 targets before gene activation. Neuronal survival was not compromised; instead, there was a reduction in subtype-specific gene expression and a progressive impairment of dopaminergic and serotonergic neuronal function, leading to behavioral deficits characteristic of Parkinson's disease and anxiety. Single-cell analysis revealed subtype-specific vulnerability to loss of PRC2 repression in dopamine neurons of the substantia nigra. Our study reveals that a PRC2-dependent nonpermissive chromatin state is essential to maintain the subtype identity and function of dopaminergic and serotonergic neurons.

| S-EPMC9417181 | biostudies-literature

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [ChIP-Seq]

Project description:Neurons of the CNS must maintain their distinct identity over an entire lifespan. Apart from instructive information provided by transcription factors driving neuron specific genes, other gene programs need to be permanently silenced. The mechanisms governing enduring gene-silencing in neurons are largely unknown, as are the consequences if they fail. Here we show that loss of the Polycomb repressive complex 2 (PRC2) obligate unit Eed in differentiated murine midbrain dopamine (mDA) neurons resulted in progressive loss of the H3K27me3 histone modification followed by upregulation of PRC2 targets, also highly enriched for the constitutive heterochromatin H3K9me3 modification. This was followed by reduced expression of mDA neuron-identity genes, particularly evident in the Substantia nigra pars compacta. Consequently, mDA-neuronal function was severely disrupted, causing parkinsonian-like motor skill deficits. Deletion of Eed in differentiated serotonergic (5HT) neurons resulted in a similar upregulation of PRC2-targets and reduced expression of genes defining 5HT neurons, which promoted loss of serotonergic identity followed by loss of function and altered behaviour. Overall, our results reveal that PRC2 inactivation leads to a selective and progressive loss of mDA or 5HT neuronal identity and function, but not to any loss of cells. Thus, our study shows that PRC2-dependent maintenance of neuronal identity is essential and safeguards against expression of other non-relevant gene programs and loss of neuronal function.

2022-07-11 | GSE189017 | GEO

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [snRNA-Seq]

2022-07-11 | GSE189329 | GEO

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [bulk RNA-Seq]

2022-07-11 | GSE189328 | GEO

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

| PRJNA781198 | ENA

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [ChIP-Seq]

Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [ChIP-Seq]

| PRJNA781201 | ENA

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [snRNA-Seq]

Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [snRNA-Seq]

| PRJNA782566 | ENA

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [bulk RNA-Seq]

Project description:PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons [bulk RNA-Seq]

| PRJNA782568 | ENA

Two eARCHT3.0 Lines for Optogenetic Silencing of Dopaminergic and Serotonergic Neurons.

Project description:Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, dysfunction of these neurons is involved in both degenerative and psychiatric disorders. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channelrhodopsin to readily enable cell-type specific activation. However, corresponding lines to silence these monoaminergic neurons have been lacking. We have generated two BAC transgenic mouse lines expressing the outward proton pump, enhanced ArchT3.0 (eArchT3.0), and GFP under control of the regulatory elements of either the dopamine transporter (DAT; Jax# 031663) or the tryptophan hydroxylase 2 (TPH2; Jax# 031662) gene locus. We demonstrate highly faithful and specific expression of these lines in dopaminergic and serotonergic neurons respectively. Additionally we validate effective and sensitive eArchT3.0-mediated silencing of these neurons using slice electrophysiology as well as with a well-established behavioral assay. These new transgenic tools will help expedite the study of dopaminergic and serotonergic system function in normal behavior and disease.

| S-EPMC6367884 | biostudies-literature

The divergent nodes of non-autonomous UPRER signaling through serotonergic and dopaminergic neurons

Project description:Performed RNA-seq analysis of animals with xbp-1s overexpression (ER stress response transcription factor) in specific neuron types: pan-neuronal, serotonergic neuron, dopaminergic neuron, and both serotonergic and dopaminergic neurons, all compared to a wild-type control. RNA-seq was performed on purified RNA extracted from ~1000 whole worms using a proprietary Genewiz protocol described briefly in the manuscript. 3 biological replicates are provided for each sample.

2021-01-01 | E-MTAB-9771 | biostudies-arrayexpress

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