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Dopamine Signaling leads to loss of Polycomb Repression and Aberrant Gene [ChIP-Seq]

ABSTRACT: Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells and through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark, H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminal differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing the dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinsons disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE60702 | GEO | 2014/10/01

SECONDARY ACCESSION(S): PRJNA259418

REPOSITORIES: GEO

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Dopamine Signaling leads to loss of Polycomb Repression and Aberrant Gene [RNA-Seq]

Project description:Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells and through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark, H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminal differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing the dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinsons disease. 12 mice were used for RNAseq, 4 conditions, 3 mice per condition.

2014-10-01 | E-GEOD-60701 | biostudies-arrayexpress

Dopamine Signaling leads to loss of Polycomb Repression and Aberrant Gene [ChIP-Seq]

Project description:Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells and through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark, H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminal differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing the dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinsons disease. 8 ChIP-seq libraries were generated from a pool of chromatin generated from 45 mice.

2014-10-01 | E-GEOD-60702 | biostudies-arrayexpress

Dopamine Signaling leads to loss of Polycomb Repression and Aberrant Gene [RNA-Seq]

2014-10-01 | GSE60701 | GEO

Zebrafish 24hpf whole embryo MZezh2mutant

Project description:Polycomb group (PcG) proteins are transcriptional repressors important to maintain cell identity during embryonic development. Ezh2, the catalytic subunit of the Polycomb Repressive Complex 2, is responsible for placing the epigenetic repressive mark histone H3 lysine 27 trimethylation (H3K27me3). In contrast to results in mouse models, zebrafish embryos mutant for both maternal and zygotic ezh2 (MZezh2) can form a normal body plan at 1 day post fertilization (dpf) but die at 2 dpf, exhibiting pleiotropic phenotypes. To elucidate the specificity of PcG-mediated repression during early zebrafish development, we conducted in depth analysis of the transcriptome, epigenome, and proteome of the MZezh2 mutant embryos at 1 dpf. We found that, despite modifications in the epigenetic landscape, transcriptome and proteome analysis revealed only minor changes in gene and protein expression levels.

2019-09-09 | PXD010922 | Pride

Chromatin immunoprecipitation of mouse polycomb group (PcG) proteins in embryonic stem cells

Project description:Polycomb group (PcG) proteins are highly conserved from flies to mammals and many of these factors have essential roles in early embryonic development. PcG proteins comprise two multimeric complexes, the Polycomb Repressive complexes 1 and 2 (PRC1 and 2), which have been shown to repress transcription through epigenetic modification of chromatin structure. To gain insight into the role of Polycomb in early development, we have identified PRC1 and PRC2 target genes in mouse embryonic stem (ES) cells using genome-scale location analysis. We found that PRC2 occupies many genes that encode key regulators of development including those encoding transcription factors and components of signaling pathways. These genes are repressed and contain nucleosomes methylated at lysine 27 on histone H3. The majority of PRC2 bound and methylated target genes are co-occupied by PRC1 indicating that these complexes function at a similar set of genes in ES cells. Lack of PRC1 or PRC2 subunits in ES cells results in derepression of target genes and loss of pluripotency. These results provide insight into how PcG proteins contribute to the maintenance of stem cell identity.

2006-05-09 | E-WMIT-12 | biostudies-arrayexpress

Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia II

Project description:L-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine replacement therapy with L-DOPA for the treatment of Parkinson disease (PD). We found repeated L-DOPA exposure induces unique transcriptional behavior in striatal neurons that is associated with the development of dyskinetic behaviors. These results suggest the development of a long-term neuronal engram underlying the persistence of LID .

2023-12-31 | GSE250362 | GEO

Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia I

2023-12-31 | GSE250361 | GEO

5C with wild type mESC, wild type NPC and mESC with various PcG components knocked-out

Project description:Master regulatory genes require stable silencing by the Polycomb-Group (PcG) to prevent improper expression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in mouse ES cells and neural progenitors using high-resolution 5C technology and super-resolution microscopy. The genomic loci of repressed PcG target genes formed discrete, small domains of tight interaction that corresponded to locations bound by canonical Polycomb Repressive Complex 1 (PRC1). These domains changed during differentiation as PRC1 binding changed. Their formation depended upon the Polyhomeotic component of canonical PRC1, and occurred independently of PRC1-catalyzed ubiquitylation. PRC1 domains differ from topologically associating domains in numerous aspects . These domains have the potential to play a key role in transmitting epigenetic silencing of PcG targets by linking PRC1 to formation of a repressive higher order structure.

2017-02-03 | GSE89948 | GEO

RNA-Seq with wild type mESC, wild type NPC and Phc1 knock-out ESC

2017-02-03 | GSE89945 | GEO

ChIP-Seq with wild type mESC and NPC

Project description:Master regulatory genes require stable silencing by the Polycomb-Group (PcG) to prevent improper expression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in mouse ES cells and neural progenitors using high-resolution 5C technology and super-resolution microscopy. The genomic loci of repressed PcG target genes formed discrete, small domains of tight interaction that corresponded to locations bound by canonical Polycomb Repressive Complex 1 (PRC1). These domains changed during differentiation as PRC1 binding changed. Their formation depended upon the Polyhomeotic component of canonical PRC1, and occurred independently of PRC1-catalyzed ubiquitylation. PRC1 domains differ from topologically associating domains in numerous aspectsá. These domains have the potential to play a key role in transmitting epigenetic silencing of PcG targets by linking PRC1 to formation of a repressive higher order structure.

2017-02-03 | GSE89929 | GEO

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