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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Morphine leads to global genome changes in H3K27me3 levels via a Polycomb Repressive Complex 2 (PRC2) self-regulatory
Iraia Muñoa-Hoyos1,2, John A Halsall3, Manu Araolaza1
1Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940, Leioa, Bizkaia, Spain.
Background:
Environmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how they sometimes persist into adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explored the role of the H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine.
Results:
Using mouse embryonic stem cells as a model system, we found that chronic morphine treatment induces a global downregulation of the histone modification H3K27me3. Conversely, ChIP-Seq showed a remarkable increase in H3K27me3 levels at specific genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. Through a self-regulatory mechanism, morphine downregulated the transcription of PRC2 components responsible for H3K27me3 by enriching high H3K27me3 levels at the promoter region. Downregulation of PRC2 components persisted for at least 48 h (4 cell cycles) following morphine removal, though promoter H3K27me3 levels returned to control levels.
Conclusions:
Morphine induces targeting of the PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and a global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K27me3 levels revert to normal sooner than global H3K27me3 or PRC2 component transcript levels. We suggest that H3K27me3 is involved in initiating morphine-induced changes in gene expression, but not in their maintenance. Model of Polycomb repressive complex 2 (PRC2) and H3K27me3 alterations induced by chronic morphine exposure. Morphine induces H3K27me3 enrichment at promoters of genes encoding core members of the PRC2 complex and is associated with their transcriptional downregulation.
Insights
Morphine exposure alters epigenetic marks like H3K27me3 in developing embryos, affecting gene expression. These changes, mediated by the PRC2 complex, can initiate developmental disruptions.
Area of Science:
- Epigenetics
- Developmental Biology
- Toxicology
Background:
- Environmentally induced epigenetic changes can impact health, but mechanisms are unclear.
- Morphine crosses the placenta, potentially causing abnormal embryo development with unknown mechanisms.
- The role of H3K27me3/PRC2 in morphine-induced developmental effects and epigenetic memory is unexplored.
Purpose of the Study:
- To investigate morphine-induced chromatin alterations in embryo development.
- To explore the role of the H3K27me3/PRC2 complex in gene expression and epigenetic inheritance following morphine exposure.
Main Methods:
- Utilized mouse embryonic stem cells as a model system.
- Employed Chromatin Immunoprecipitation sequencing (ChIP-Seq) to analyze H3K27me3 levels.
- Investigated the impact of chronic morphine treatment on gene expression and epigenetic modifications.
Main Results:
- Chronic morphine treatment globally downregulated H3K27me3 but increased it at specific gene promoters.
- Morphine disrupted genes critical for embryo development, cell cycle, and metabolism.
- A self-regulatory mechanism showed morphine downregulating PRC2 components via promoter enrichment of H3K27me3.
Conclusions:
- Morphine targets the PRC2 complex to promoters, altering gene expression and reducing global H3K27me3.
- H3K27me3 initiates morphine-induced gene expression changes, but PRC2 component downregulation maintains them.
- Epigenetic changes initiated by morphine may persist beyond drug removal, impacting development.
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