Epigenetic regulation of kappa opioid receptor gene in neuronal differentiation

Park, Sung Wook; He, Yayi; Ha, Sung Gil; Loh, Horace H.; Wei, Li‐Na

doi:10.1016/j.neuroscience.2007.12.015

Cited by 17 publications

(22 citation statements)

References 43 publications

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“…The current research, demonstrating the effects of stress on KOR epigenetic processes is in line with the indicated ability of external stimuli, including stressors such as forced swim exposure, to affect chromatin remodeling, DNA methylation, and histone modification of stress-associated genes and/or within stress-sensitive brain area (25). The change in c-Myc is most significant, which is consistent with studies of cell cultures (26)(27)(28). The increased acetylation of histone 4, reduced lysine dimethylation of histone 3, and reduced binding of HDAC1 are also consistent with changes on Pr1 chromatin in studying cultured cells where this promoter is found to be active (36).…”

Section: Discussionsupporting

confidence: 88%

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Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Flaisher-Grinberg

Persaud

Loh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Exposure to stress is associated with adverse emotional and behavioral responses. Whereas the κ-opioid receptor (KOR) system is known to mediate some of the effects, it is unclear whether and how stress affects epigenetic regulation of this gene. Because the KOR gene can use two promoters (Pr1 and Pr2) and two polyadenylation signals (PA1 and PA2), it is also interesting whether and how these distinct regulatory mechanisms are differentially modulated by stress. The current study examined the effects of stress on these different regulatory mechanisms of the KOR gene. Results showed that stress selectively increased the expression of KOR mRNA isoforms controlled by Pr1 and terminated at PA1 in specific brain areas including the medial-prefrontal cortex, hippocampus, brainstem, and sensorimotor cortex, but not in the amygdala or hypothalamus. These effects correlated with altered epigenetic state of KOR Pr1 chromatin, as well as elevation and increased recruitment of the principal transcription factor c-Myc, which could activate Pr1. Stress-induced modulation of Pr1 was further validated using glutamate-sensitive murine hippocampal cell line, HT22. The results revealed a common molecular mechanism underlying the effect of stress on selected chromatin regions of this gene at the cellular level and in the context of whole animal and identified a critical role for c-Myc in stress-triggered epigenetic regulation of the KOR gene locus. This study sheds light on the mechanisms of stress-induced epigenetic regulation that targets specific chromatin segments and suggests certain KOR transcripts and its principal transcription factor c-Myc as potential targets for brain-area-specific intervention.

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Section: Discussionsupporting

confidence: 88%

“…Epigenetic regulation of the KOR gene in culture systems includes inputs like retinoic acid, nitric oxide and nerve growth factor (26)(27)(28)(29). However, whether and how the diverse promoter regions and PA sites of the KOR gene are subjected to differential epigenetic regulation in animals is unclear.…”

mentioning

confidence: 99%

Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Flaisher-Grinberg

Persaud

Loh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Whether and how these effectors contribute specifically to EGF-stimulated neurite outgrowth needs to be evaluated in the future. Opioid receptors have been shown to be involved in neuronal differentiation (37)(38)(39). This study adds a functional role for KOR in the development of the nervous system, specifically in neurite/axon extension.…”

Section: Signal Of Egf To Stimulate Kor/dynorphin-dependent Axon Extementioning

confidence: 70%

Kappa opioid receptor contributes to EGF-stimulated neurite extension in development

Tsai

Tsui

Pintar

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor (EGF), a mitogen, also stimulates neurite extension during development, but the underlying mechanism is elusive. This study reveals a functional role for kappa opioid receptor (KOR) in EGF-stimulated neurite extension, and the underlying mechanism. EGF and activated EGF receptor (EGFR) levels are elevated in embryonic spinal cords during late gestation stages, with concurrent rise in protein levels of KOR and axon extension markers, growth-associated protein 43 (GAP43), and transient axonal glycoprotein-1 (TAG-1). Both GAP43 and TAG-1 levels are significantly lower in KOR-null (KOR −/− ) spinal cords, and EGFR inhibitors effectively reduce the levels of KOR, GAP43, and TAG-1 in wildtype embryonic spinal cords. For KOR −/− or KOR-knockdown dorsal root ganglion (DRG) neurons, EGF can no longer effectively stimulate axon extension, which can be rescued by introducing a constitutive KOR expressing vector but not by a regulated KOR vector carrying its 5′ untranslated region, which can be bound and repressed by growth factor receptor-bound protein 7 (Grb7). Furthermore, blocking KOR activation by application of anti-dynorphin, KOR antagonist, or EGFR inhibitor effectively reduces axon extension of DRG neurons. Thus, EGF-stimulated axon extension during development is mediated, at least partially, by specific elevation of KOR protein production at posttranscriptional level, as well as activation of KOR signaling. The result also reveals an action of EGF to augment posttranscriptional regulation of certain mRNAs during developmental stages.5′ untranslated region | dorsal root ganglion | epidermal growth factor | growth factor receptor-bound protein 7 | posttranscriptional regulation

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“…Two recent studies found that H3K4 dimethylation, a marker of transcriptional activity, was enhanced in the promoter region of neuron-specific opioid receptors, whereas H3K9 trimethylation, a marker of transcriptional repression, was reduced (51,265). Another study found that the histone H3K27-specific histone demethylase JMJD3 is necessary for neural differentiation, as it demethylates H3K27, a modification indicating transcriptional repression, at the neuron-specific nestin promoter (38).…”

Section: Neural Differentiationmentioning

confidence: 99%

Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes

Gräff

Kim

Dobbin

et al. 2011

Physiological Reviews

322

246

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Over the past decade, it has become increasingly obvious that epigenetic mechanisms are an integral part of a multitude of brain functions that range from the development of the nervous system over basic neuronal functions to higher order cognitive processes. At the same time, a substantial body of evidence has surfaced indicating that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are in part caused by aberrant epigenetic modifications. Because of their inherent plasticity, such pathological epigenetic modifications are readily amenable to pharmacological interventions and have thus raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. In this review, we give a detailed overview of the implication of epigenetic mechanisms in both physiological and pathological brain processes and summarize the state-of-the-art of “epigenetic medicine” where applicable. Despite, or because of, these new and exciting findings, it is becoming apparent that the epigenetic machinery in the brain is highly complex and intertwined, which underscores the need for more refined studies to disentangle brain-region and cell-type specific epigenetic codes in a given environmental condition. Clearly, the brain contains an epigenetic “hotspot” with a unique potential to not only better understand its most complex functions, but also to treat its most vicious diseases.

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Epigenetic regulation of kappa opioid receptor gene in neuronal differentiation

Cited by 17 publications

References 43 publications

Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Kappa opioid receptor contributes to EGF-stimulated neurite extension in development

Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes

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