Morphine leads to global genome changes in H3K27me3 levels via a Polycomb Repressive Complex 2 (PRC2) self-regulatory mechanism in mESCs

Abstract

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. Graphic abstract 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.

Histone modifications in cocaine, methamphetamine and opioids

“…Compared to acetylation, the understanding of how opioids regulate histone methylation is superficial. Only specific histone tail residues---H3K9 and H3K27 have been identified in opioid treatment [ [90] , [91] , [92] ]. Repeated opioid exposure reduces H3K9Me2 in NAc and the central nucleus of the amygdala, and chronic opioid treatment appears to promote transcriptional activities [ 92 ].…”

“…Following morphine withdrawal, the levels of enhanced promoter H3K27Me3 return to normal first in general level. It indicates that H3K27Me3 is involved in the formation of morphine-induced characteristic changes, but not in their maintenance [ 90 ].…”

Hypoxic condition induced H3K27me3 modification of the LncRNA Tmem235 promoter thus supporting apoptosis of BMSCs

“…The methylation modification of H3K27 is mainly regulated by polycomb repressive complex 2 (PRC2), the core catalytic unit of which is the enhancer of zeste homolog 2 (EZH2). Moreover, the C-terminal (C-ter) SET domain of PRC2 catalyzes the methylation of H3K27 to H3K27me3 [19][20][21]. Moreover, the lysine demethylase 6 (KDM6) family of proteins mediates H3K27me3 demethylation, such as that of KDM6A and KDM6B [22,23].…”