Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation

Arifuzzaman, Sarder; Das, Amitabh; Kim, Sun Hwa; Yoon, Tae-Ho; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

doi:10.1016/j.bcp.2017.04.016

Cited by 35 publications

(31 citation statements)

References 60 publications

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“…Inhibition of EZH2 attenuates the expression of inflammatory mediators ( Table 2 ) and the development and maintenance of mechanical and thermal hyperalgesia in rats with PSL. In agreement with this study, Arifuzzaman et al (2017) described that the use of EPZ-6438, an EZH2 inhibitor, dose-dependently inhibits LPS induced inflammatory gene expression in microglial cells in vitro . Genes found to be decreased by EZH2 inhibition after LPS activation were linked to cytokines, chemokines, enzymes, and transcription factors ( Arifuzzaman et al, 2017 ).…”

Section: Induction Of Pro-inflammatory Neuromodulator Expressionsupporting

confidence: 88%

“…In agreement with this study, Arifuzzaman et al (2017) described that the use of EPZ-6438, an EZH2 inhibitor, dose-dependently inhibits LPS induced inflammatory gene expression in microglial cells in vitro . Genes found to be decreased by EZH2 inhibition after LPS activation were linked to cytokines, chemokines, enzymes, and transcription factors ( Arifuzzaman et al, 2017 ). Thus, targeting the EZH2 signaling pathway could be an effective approach for the management of neuropathic pain, through immunomodulation.…”

Section: Induction Of Pro-inflammatory Neuromodulator Expressionsupporting

confidence: 88%

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Epigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma

Penas

Navarro

2018

Front. Cell. Neurosci.

104

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Accumulating evidence suggests that epigenetic alterations lie behind the induction and maintenance of neuropathic pain. Neuropathic pain is usually a chronic condition caused by a lesion, or pathological change, within the nervous system. Neuropathic pain appears frequently after nerve and spinal cord injuries or diseases, producing a debilitation of the patient and a decrease of the quality of life. At the cellular level, neuropathic pain is the result of neuronal plasticity shaped by an increase in the sensitivity and excitability of sensory neurons of the central and peripheral nervous system. One of the mechanisms thought to contribute to hyperexcitability and therefore to the ontogeny of neuropathic pain is the altered expression, trafficking, and functioning of receptors and ion channels expressed by primary sensory neurons. Besides, neuronal and glial cells, such as microglia and astrocytes, together with blood borne macrophages, play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as pro-inflammatory cytokines and chemokines, which enhance neuronal excitability. Altered gene expression of neuronal receptors, ion channels, and pro-inflammatory cytokines and chemokines, have been associated to epigenetic adaptations of the injured tissue. Within this review, we discuss the involvement of these epigenetic changes, including histone modifications, DNA methylation, non-coding RNAs, and alteration of chromatin modifiers, that have been shown to trigger modification of nociception after neural lesions. In particular, the function on these processes of EZH2, JMJD3, MeCP2, several histone deacetylases (HDACs) and histone acetyl transferases (HATs), G9a, DNMT, REST and diverse non-coding RNAs, are described. Despite the effort on developing new therapies, current treatments have only produced limited relief of this pain in a portion of patients. Thus, the present review aims to contribute to find novel targets for chronic neuropathic pain treatment.

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Section: Induction Of Pro-inflammatory Neuromodulator Expressionsupporting

confidence: 88%

Section: Induction Of Pro-inflammatory Neuromodulator Expressionsupporting

confidence: 88%

Epigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma

Penas

Navarro

2018

Front. Cell. Neurosci.

104

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“…Chromatin Immunoprecipitation experiments were performed as previously described ( 35 ). Briefly, chromatin from 1 × 10 7 cells was used for each immunoprecipitation.…”

Section: Methodsmentioning

confidence: 99%

High-Resolution Mapping and Dynamics of the Transcriptome, Transcription Factors, and Transcription Co-Factor Networks in Classically and Alternatively Activated Macrophages

et al. 2018

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Macrophages are the prime innate immune cells of the inflammatory response, and the combination of multiple signaling inputs derived from the recognition of host factors [e.g., interferon-g (IFN-γ)] and invading pathogen products (e.g., toll-like receptors (TLRs) agonists) are required to maintain essential macrophage function. The profound effects on biological outcomes of inflammation associated with IFN-γ pretreatment (“priming”) and TLR4 ligand bacterial lipopolysaccharide (LPS)-induced macrophage activation (M1 or classical activation) have long been recognized, but the underlying mechanisms are not well defined. Therefore, we analyzed gene expression profiles of macrophages and identified genes, transcription factors (TFs), and transcription co-factors (TcoFs) that are uniquely or highly expressed in IFN-γ-mediated TLR4 ligand LPS-inducible versus only TLR4 ligand LPS-inducible primary macrophages. This macrophage gene expression has not been observed in macrophage cell lines. We also showed that interleukin (IL)-4 and IL-13 (M2 or alternative activation) elicited the induction of a distinct subset of genes related to M2 macrophage polarization. Importantly, this macrophage gene expression was also associated with promoter conservation. In particular, our approach revealed novel roles for the TFs and TcoFs in response to inflammation. We believe that the systematic approach presented herein is an important framework to better understand the transcriptional machinery of different macrophage subtypes.

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“…[96][97][98][99] Several studies have reported EZH2 plays important role in ROS generation, cardiac hypertrophy and inflammation. [100][101][102] Indeed, increased EZH2 expression blunts SOD-2 expression leading to increase ROS generation that contributes to progression of pulmonary artery hypertension. 100 A recent study demonstrated that targeting EZH2 in erythroid cells exposed to ferric nitrilotriacetate and cobalt-60 radiation protects against oxidative stress.…”

Section: The Role Of Epigenetics In Cardiometabolic Diseasesmentioning

confidence: 99%

“…106 In addition, specific inhibition of EZH2 by a small molecule inhibitor protects against neuro-inflammation in microglial cells. 102 Indeed, EZH2-dependent conformational changes promote accumulation of free radicals and inflammation. 100,107 Lastly, EZH2 is required for NF-κB signaling in cancer.…”

Section: The Role Of Epigenetics In Cardiometabolic Diseasesmentioning

confidence: 99%

Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc

Costantino

Paneni

Mitchell

et al. 2018

International Journal of Cardiology

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Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation

Cited by 35 publications

References 60 publications

Epigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma

Epigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma

High-Resolution Mapping and Dynamics of the Transcriptome, Transcription Factors, and Transcription Co-Factor Networks in Classically and Alternatively Activated Macrophages

Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc

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