RESEARCH HIGHLIGHTS Nature Reviews Neuroscience | AOP, published online 4 March 2015; doi:10.1038/nrn3933
GENE EXPRESSION
Putting a stop to BDNF
Jen nie Va llis /N PG
Chronic administration of morphine reduces brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) and also enhances the rewarding properties of this drug. The mechanisms underlying the morphine-induced reductions in BDNF expression are unknown, but now Koo et al. identify a series of epigenetic modifications that are involved in this response. First, the authors showed that there is reduced BDNF expression both in VTAs from humans addicted to heroin and in VTAs of rats that had chronically selfadministered heroin. In rats, chronic morphine administration also resulted in reduced BDNF expression in this brain reward region. To determine the underlying mechanism, the authors used quantitative PCR (qPCR) to show that expression levels of exons II, IV and VI of Bdnf were reduced in the VTA following chronic exposure to morphine; this reduction persisted for at least 2 weeks after cessation of morphine
exposure, suggesting that the underlying mechanism was likely to be epigenetic. RNA polymerase II (Pol II) transcribes Bdnf, and stalled Pol II is associated with stalled (suppressed) transcription. Using quantitative chromatin immunoprecipitation (qChIP) to detect patterns of Pol II phosphorylation associated with stalled Pol II, the authors found that chronic morphine treatment resulted in increased binding of stalled Pol II to several promoter regions of Bdnf (including the promoters for exons II, IV and VI). Moreover, the authors found that chronic morphine altered histone regulation of Bdnf in the VTA: again using qChIP, they determined that chronic morphine increased binding of certain important histonemodifying enzymes and related regulatory proteins to Bdnf, which is consistent with transcriptional repression of this gene. Expression of activated cyclic AMP-responsive element-binding protein (CREB; which is known to induce Bdnf expression)
was decreased at Bdnf promoters corresponding to exons I, II, IV and VI. Similarly, knockdown of Creb decreased Bdnf mRNA in VTAs of rats that were given chronic morphine treatment. The nuclear receptor NURR1 is a transcription factor that is known to positively regulate the expression of BDNF in midbrain dopamine neurons and is also a downstream target of CREB. The expression of Nurr1 mRNA was suppressed in chronic-morphinetreated rats, and NURR1 binding to certain Bdnf promoters was also decreased in the VTA. Furthermore, chronic morphine treatment decreased binding of activated CREB to the Nurr1 promoter in the VTA, suggesting that reduced CREB-induced NURR1 expression is involved in the suppression of Bdnf induced by chronic morphine. The morphine-induced exclusion of activated CREB from the Bdnf and Nurr1 promoters in the VTA was associated with a particular morphine-induced histone modification at these genes, thus linking chromatin to transcriptional regulation by morphine. Overall, this study reveals various epigenetic mechanisms that are induced by chronic morphine treatment that contribute to suppression of Bdnf expression in the VTA. Sian Lewis ORIGINAL RESEARCH PAPER Koo, J. W. et al. Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nature Neurosci. http://dx.doi.org/10.1038/ nn.3932 (2015)
NATURE REVIEWS | NEUROSCIENCE
chronic morphine increased binding of certain important histonemodifying enzymes … to Bdnf, which is consistent with transcriptional repression
VOLUME 16 | APRIL 2015 © 2015 Macmillan Publishers Limited. All rights reserved
GENE EXPRESSION
Putting a stop to BDNF
Jen nie Va llis /N PG
Chronic administration of morphine reduces brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) and also enhances the rewarding properties of this drug. The mechanisms underlying the morphine-induced reductions in BDNF expression are unknown, but now Koo et al. identify a series of epigenetic modifications that are involved in this response. First, the authors showed that there is reduced BDNF expression both in VTAs from humans addicted to heroin and in VTAs of rats that had chronically selfadministered heroin. In rats, chronic morphine administration also resulted in reduced BDNF expression in this brain reward region. To determine the underlying mechanism, the authors used quantitative PCR (qPCR) to show that expression levels of exons II, IV and VI of Bdnf were reduced in the VTA following chronic exposure to morphine; this reduction persisted for at least 2 weeks after cessation of morphine
exposure, suggesting that the underlying mechanism was likely to be epigenetic. RNA polymerase II (Pol II) transcribes Bdnf, and stalled Pol II is associated with stalled (suppressed) transcription. Using quantitative chromatin immunoprecipitation (qChIP) to detect patterns of Pol II phosphorylation associated with stalled Pol II, the authors found that chronic morphine treatment resulted in increased binding of stalled Pol II to several promoter regions of Bdnf (including the promoters for exons II, IV and VI). Moreover, the authors found that chronic morphine altered histone regulation of Bdnf in the VTA: again using qChIP, they determined that chronic morphine increased binding of certain important histonemodifying enzymes and related regulatory proteins to Bdnf, which is consistent with transcriptional repression of this gene. Expression of activated cyclic AMP-responsive element-binding protein (CREB; which is known to induce Bdnf expression)
was decreased at Bdnf promoters corresponding to exons I, II, IV and VI. Similarly, knockdown of Creb decreased Bdnf mRNA in VTAs of rats that were given chronic morphine treatment. The nuclear receptor NURR1 is a transcription factor that is known to positively regulate the expression of BDNF in midbrain dopamine neurons and is also a downstream target of CREB. The expression of Nurr1 mRNA was suppressed in chronic-morphinetreated rats, and NURR1 binding to certain Bdnf promoters was also decreased in the VTA. Furthermore, chronic morphine treatment decreased binding of activated CREB to the Nurr1 promoter in the VTA, suggesting that reduced CREB-induced NURR1 expression is involved in the suppression of Bdnf induced by chronic morphine. The morphine-induced exclusion of activated CREB from the Bdnf and Nurr1 promoters in the VTA was associated with a particular morphine-induced histone modification at these genes, thus linking chromatin to transcriptional regulation by morphine. Overall, this study reveals various epigenetic mechanisms that are induced by chronic morphine treatment that contribute to suppression of Bdnf expression in the VTA. Sian Lewis ORIGINAL RESEARCH PAPER Koo, J. W. et al. Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nature Neurosci. http://dx.doi.org/10.1038/ nn.3932 (2015)
NATURE REVIEWS | NEUROSCIENCE
chronic morphine increased binding of certain important histonemodifying enzymes … to Bdnf, which is consistent with transcriptional repression
VOLUME 16 | APRIL 2015 © 2015 Macmillan Publishers Limited. All rights reserved
