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

Abstract

Schwann cell myelination is tightly regulated by timely expression of key transcriptional regulators that respond to specific environmental cues, but the molecular mechanisms underlying such a process are poorly understood. We found that the acetylation state of NF-κB, which is regulated by histone deacetylases (HDACs) 1 and 2, is critical for orchestrating the myelination program. Mice lacking both HDACs 1 and 2 (HDAC1/2) exhibited severe myelin deficiency with Schwann cell development arrested at the immature stage. NF-κB p65 became heavily acetylated in HDAC1/2 mutants, inhibiting the expression of positive regulators of myelination and inducing the expression of differentiation inhibitors. We observed that the NF-κB protein complex switched from associating with p300 to associating with HDAC1/2 as Schwann cells differentiated. NF-κB and HDAC1/2 acted in a coordinated fashion to regulate the transcriptionally linked chromatin state for Schwann cell myelination. Thus, our results reveal an HDAC-mediated developmental switch for controlling myelination in the peripheral nervous system.

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Figure 1: Ablation of HDAC1 and HDAC2 in the Schwann cell lineage results in severe myelination defects in sciatic nerves.
Figure 2: Effects of HDAC1 and HDAC2 deletion on Schwann cell precursor formation and differentiation.
Figure 3: p65 subunit of NF-κB is an important substrate of HDAC1 and HDAC2 for Schwann cell differentiation.
Figure 4: The acetylation state of NF-κB regulated by HDAC1 and HDAC2 is critical for the Schwann cell differentiation program.
Figure 5: HDAC1 and HDAC2 and NF-κB cooperate to regulate epigenetic marks on the critical genes for Schwann cell differentiation.
Figure 6: Activation of canonical Wnt/β-catenin signaling does not inhibit Schwann cell myelination.

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Acknowledgements

We would like to thank D. Meijer for Dhh-cre mice, B. Carter and J. Chan for critical comments, and P. Casaccia for initial discussions. We thank Q. Weng and Z. Ma for technical support, O. Nakagawa and J. Chen for the p300/CBP and p65/RelA expression vectors, and R. Kageyama for the Hes5 luciferase reporter. This study was funded in part by grants from the US National Institutes of Health (NS072427) and the National Multiple Sclerosis Society (RG3978) to Q.R.L.

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Contributions

Y.C. conducted the majority of the experiments and analyzed the data. H.W. and X.X. contributed to HDAC mutant generation, phenotype analysis and biochemical assays. S.O.K., J.S. and H.A.S. provided reagents and input. M.H. provided the p65 mutant–expression vectors. K.A.N. provided CNP-Cre mice for initial phenotype observation. E.N.O. provided loxP-flanked HDAC1 and HDAC2 mice and inputs. Q.R.L. supervised the project, analyzed the data and wrote the manuscript.

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Correspondence to Q Richard Lu.

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The authors declare no competing financial interests.

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Chen, Y., Wang, H., Yoon, S. et al. HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination. Nat Neurosci 14, 437–441 (2011). https://doi.org/10.1038/nn.2780

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