HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination

Chen, Ying; Wang, Haibo; Yoon, Sung Ok; Xu, Xiaomei; Hottiger, Michael O.; Svaren, John; Nave, Klaus‐Armin; Kim, Haesun A.; Olson, Eric N.; Lü, Qing

doi:10.1038/nn.2780

Cited by 167 publications

(162 citation statements)

References 23 publications

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“…It is known that activation of the angiotensin system induces Smad3 phosphorylation and oxidative stress [29][30][31] whereas HDAC interacts with the NFkB pathway. 32 Our findings are consistent with our computational predictions. These results support that SAHA and benazepril probably affect distinct pathways in the diseased kidney.…”

Section: Pathway Validation In Kidneys Of Mice Treated With Benazeprisupporting

confidence: 91%

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Zhong

Chen

Liu

et al. 2013

Journal of the American Society of Nephrology

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The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases. In addition, this study provides proof-of-concept that drug-induced expression signatures have potential use in predicting the effects of combination drug therapy.

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Section: Pathway Validation In Kidneys Of Mice Treated With Benazeprisupporting

confidence: 91%

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Zhong

Chen

Liu

et al. 2013

Journal of the American Society of Nephrology

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“…The lysate was incubated with HA binding resin at 4°C for 2 hours. At that point, the bait was eluted 3 times using excess HA peptide (1 mg/ml in 20 mM Tris-HCl [pH 7.4], 100 mM Moreover, NF-κB plays an important role in neuronal function and learning processes (41,42) and is similarly important for myelination and Schwann cell function (43). Therefore, the alterations in the NF-κB pathway seen in these patients may contribute to their neurologic phenotype.…”

Section: Figurementioning

confidence: 99%

CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling

Starokadomskyy¹,

Gluck²,

Li³

et al. 2013

J. Clin. Invest.

100

135

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NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.

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“…There is general agreement that histone deacetylases play an essential function in regulating differentiation of neural precursor cells to oligodendrocytes in the developing brain in rodents (MarinHusstege et al, 2002;Shen et al, 2005;Ye et al, 2009;Chen et al, 2011;Jacob et al, 2011). It was reported that genetic ablation of HDAC1 and HDAC2 in the mouse blocks oligodendrocyte differentiation by activation of Wnt/beta catenin signaling pathway.…”

Section: The Involvement Of Hdac1 and Hdac2 In Neurogenesismentioning

confidence: 99%

Histone deacetylases 1 and 2 are required for brain development

Jaworska

Ziemka‐Nałęcz

Zalewska³

2015

Int. J. Dev. Biol.

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Epigenetic modifications of histones have been implicated in the regulation of cell specific expression of genes required for neuronal development. The best studied post-translational (epigenetic) modification of histones is the process of reversible acetylation. Two types of enzymeshistone acetyltransferases (HATs) and histone deacetylases (HDACs) establish and maintain specific patterns of histone acetylation in balance, thereby contributing to both transcriptional activation and repression of specific sets of genes. Histone deacetylases catalyze the removal of acetyl groups from selected lysine residues in the conserved tails of core histone proteins and are considered as transcriptional corepressors. A significant amount of data implicates HDACs in diverse biological processes, including tissue specific developmental program by silencing specific growth-inhibitory genes. In line with this, gene disruption studies have shown that the class I deacetylases, HDAC1 and HDAC2 play an essential role in nervous system development. In the present review, we briefly highlight current insights supporting the function of histone deacetylases in rodent brain development and discuss present knowledge referring to their role in neurogenesis, taking into consideration results obtained in culture systems and in in vivo studies.

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HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination

Cited by 167 publications

References 23 publications

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling

Histone deacetylases 1 and 2 are required for brain development

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