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The emerging field of epigenetics in neurodegeneration and neuroprotection

An Author Correction to this article was published on 05 October 2018

Key Points

  • Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases.

  • Histone acetylation is the modification that is best understood and most tightly associated with synaptic plasticity and memory formation. The dysregulation of histone acetylation has been linked to the memory impairments that are associated with neurodegenerative diseases.

  • Emerging evidence indicates that changes in the DNA methylation status of synaptic plasticity-associated and memory-associated genes can be rapid and reversible. Members of the DNA methyltransferase (DNMT) family promote the rapid methylation and silencing of these genes, whereas the ten-eleven translocation (TET) proteins (TET1, TET2 and TET3) promote the demethylation and activation of genes that are crucial for synaptic plasticity, memory acquisition and storage.

  • Although neurodegenerative disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression.

  • Polycomb proteins orchestrate the epigenetic remodelling and silencing of genes that are involved in neuronal death, thereby enabling neurons to survive the hypoxia that is associated with ischaemic stroke.

  • Emerging evidence implicates non-coding RNAs, such as microRNAs and long non-coding RNAs, in the epigenetic remodelling of target genes that are involved in neurodegeneration.

  • Although the past decade has witnessed the development of new chromatin-modifying drugs and their advance into clinical trials in patients with brain disorders, there remains the persisting challenge of developing drugs that can penetrate the blood–brain barrier and ameliorate neurodegeneration and cognitive deficits with high specificity and minimal toxicity.

Abstract

Epigenetic mechanisms — including DNA methylation, histone post-translational modifications and changes in nucleosome positioning — regulate gene expression, cellular differentiation and development in almost all tissues, including the brain. In adulthood, changes in the epigenome are crucial for higher cognitive functions such as learning and memory. Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases. Although these disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression. Although not somatically heritable, epigenetic modifications in neurons are dynamic and reversible, which makes them good targets for therapeutic intervention.

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Figure 1: Polycomb proteins in epigenetic remodelling and neuroprotection.
Figure 2: Restrictive element 1-silencing transcription factor in neurodegenerative disease.

References

  1. Waddington, C. H. The epigenotype. 1942. Int. J. Epidemiol. 41, 10–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Sweatt, J. D. The emerging field of neuroepigenetics. Neuron 80, 624–632 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Maze, I., Noh, K. M., Soshnev, A. A. & Allis, C. D. Every amino acid matters: essential contributions of histone variants to mammalian development and disease. Nat. Rev. Genet. 15, 259–271 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Piletic, K. & Kunej, T. MicroRNA epigenetic signatures in human disease. Arch. Toxicol. 90, 2405–2419 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Saeidimehr, S., Ebrahimi, A., Saki, N., Goodarzi, P. & Rahim, F. MicroRNA-based linkage between aging and cancer: from epigenetics view point. Cell J. 18, 117–126 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Leone, S. & Santoro, R. Challenges in the analysis of long noncoding RNA functionality. FEBS Lett. 590, 2342–2353 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Roberts, T. C., Morris, K. V. & Wood, M. J. The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease. Phil. Trans. R. Soc. B 369, 20130507 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Fagiolini, M., Jensen, C. L. & Champagne, F. A. Epigenetic influences on brain development and plasticity. Curr. Opin. Neurobiol. 19, 207–212 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hwang, J. Y., Aromolaran, K. A. & Zukin, R. S. Epigenetic mechanisms in stroke and epilepsy. Neuropsychopharmacology 38, 167–182 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Day, J. J., Kennedy, A. J. & Sweatt, J. D. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annu. Rev. Pharmacol. Toxicol. 55, 591–611 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Landgrave-Gomez, J., Mercado-Gomez, O. & Guevara-Guzman, R. Epigenetic mechanisms in neurological and neurodegenerative diseases. Front. Cell. Neurosci. 9, 58 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. Miller, C. A. & Sweatt, J. D. Covalent modification of DNA regulates memory formation. Neuron 53, 857–869 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Day, J. J. & Sweatt, J. D. DNA methylation and memory formation. Nat. Neurosci. 13, 1319–1323 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Graff, J., Kim, D., Dobbin, M. M. & Tsai, L. H. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol. Rev. 91, 603–649 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Feng, J. et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13, 423–430 (2010). This paper is the first to show that DNMT1 and DNMT3A are required for synaptic plasticity, and learning and memory, and that they act via DNA methylation and regulate the expression of neuronal genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kaas, G. A. et al. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79, 1086–1093 (2013). This paper is the first to show that TET1 demethylates DNA and that its expression, independently of its catalytic activity, regulates memory formation.

    Article  CAS  PubMed  Google Scholar 

  18. Levenson, J. M. et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J. Biol. Chem. 281, 15763–15773 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Swank, M. W. & Sweatt, J. D. Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning. J. Neurosci. 21, 3383–3391 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Levenson, J. M. et al. Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 279, 40545–40559 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Korzus, E., Rosenfeld, M. G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bourtchouladze, R. et al. A mouse model of Rubinstein–Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc. Natl Acad. Sci. USA 100, 10518–10522 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Petrij, F. et al. Rubinstein–Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–351 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Blough, R. I. et al. Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein–Taybi syndrome. Am. J. Med. Genet. 90, 29–34 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L. H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007). This paper shows that environmental enrichment reinstates memory and learning after substantial neuronal loss and atrophy in a mouse model of neurodegeneration.

    Article  CAS  PubMed  Google Scholar 

  27. Calderone, A. et al. Ischaemic insults de-repress the gene silencer rest in neurons destined to die. J. Neurosci. 23, 2112–2121 (2003). This is the first paper to show that REST expression is altered in a disease state and that REST-mediated gene repression is pivotal to a cellular response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Noh, K. M. et al. Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc. Natl Acad. Sci. USA 109, E962–E971 (2012). This is the first paper to show that REST assembles with co-repressors at the promoters of transcriptionally responsive target genes and orchestrates epigenetic remodelling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ballas, N. & Mandel, G. The many faces of REST oversee epigenetic programming of neuronal genes. Curr. Opin. Neurobiol. 15, 500–506 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Ooi, L. & Wood, I. C. Chromatin crosstalk in development and disease: lessons from REST. Nat. Rev. Genet. 8, 544–554 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Baldelli, P. & Meldolesi, J. The transcription repressor REST in adult neurons: physiology, pathology, and diseases. eNeuro http://dx.doi.org/10.1523/ENEURO.0010-15.2015 (2015).

  32. Bruce, A. W. et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc. Natl Acad. Sci. USA 101, 10458–10463 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Conaco, C., Otto, S., Han, J. J. & Mandel, G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc. Natl Acad. Sci. USA 103, 2422–2427 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ballas, N., Grunseich, C., Lu, D. D., Speh, J. C. & Mandel, G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005). This is the first paper to show that REST assembles with co-repressors at the promoters of target genes and orchestrates epigenetic remodelling in neural progenitors.

    Article  CAS  PubMed  Google Scholar 

  35. Rodenas-Ruano, A., Chavez, A. E., Cossio, M. J., Castillo, P. E. & Zukin, R. S. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat. Neurosci. 15, 1382–1390 (2012). This is the first paper to show that REST assembles with co-repressors at the promoter of the gene encoding a synaptic protein (ionotropic glutamate receptor NMDA 2B (GluN2B)) and fine-tunes the expression of genes involved in synaptic plasticity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Palm, K., Metsis, M. & Timmusk, T. Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. Brain Res. Mol. Brain Res. 72, 30–39 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Huang, Y., Doherty, J. J. & Dingledine, R. Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J. Neurosci. 22, 8422–8428 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Formisano, L. et al. Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons. Proc. Natl Acad. Sci. USA 104, 4170–4175 (2007). This is the first paper to show the dysregulation of REST and REST-dependent epigenetic remodelling in a clinically relevant model of ischaemic stroke.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Formisano, L. et al. NCX1 is a new rest target gene: role in cerebral ischemia. Neurobiol. Dis. 50, 76–85 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Formisano, L. et al. Sp3/REST/HDAC1/HDAC2 complex represses and Sp1/HIF-1/p300 complex activates ncx1 gene transcription, in brain ischemia and in ischemic brain preconditioning, by epigenetic mechanism. J. Neurosci. 35, 7332–7348 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zuccato, C. et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat. Genet. 35, 76–83 (2003). This is the first paper to show that REST expression is altered in the striatal tissue of humans and mice with Huntington disease.

    Article  CAS  PubMed  Google Scholar 

  42. Zuccato, C. et al. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease. J. Neurosci. 27, 6972–6983 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schiffer, D. et al. Repressor element-1 silencing transcription factor (REST) is present in human control and Huntington's disease neurones. Neuropathol. Appl. Neurobiol. 40, 899–910 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Lu, T. et al. REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448–454 (2014). This is the first paper to show that REST is upregulated in normal ageing and that its decline is associated with the oxidative stress observed in Alzheimer disease and with the onset of Alzheimer disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Perera, A. et al. TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression. Cell Rep. 11, 283–294 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Guardavaccaro, D. et al. Control of chromosome stability by the β-TrCP–REST–Mad2 axis. Nature 452, 365–369 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Westbrook, T. F. et al. SCFβ-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452, 370–374 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Singh, A. et al. Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF(β-TRCP) in neuroblastoma cells. Cancer 117, 5189–5202 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Kaneko, N., Hwang, J. Y., Gertner, M., Pontarelli, F. & Zukin, R. S. Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death. J. Neurosci. 34, 6030–6039 (2014). This is the first paper to show that CK1 is the upstream signal that negatively regulates REST in neurons.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Huang, Z. et al. Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells. Nat. Cell Biol. 13, 142–152 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zukin, R. S. Eradicating the mediators of neuronal death with a fine-tooth comb. Sci. Signal. 3, e20 (2010).

    Article  CAS  Google Scholar 

  52. Stapels, M. et al. Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci. Signal. 3, ra15 (2010). This is the first paper to show that Polycomb proteins are activated in postmitotic vertebrate neurons and are crucial for ischaemic tolerance.

    Article  PubMed  CAS  Google Scholar 

  53. Blackledge, N. P., Rose, N. R. & Klose, R. J. Targeting Polycomb systems to regulate gene expression: modifications to a complex story. Nat. Rev. Mol. Cell Biol. 16, 643–649 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Schlesinger, Y. et al. Polycomb-mediated methylation on lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 39, 232–236 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Schratt, G. MicroRNAs at the synapse. Nat. Rev. Neurosci. 10, 842–849 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Aksoy-Aksel, A., Zampa, F. & Schratt, G. MicroRNAs and synaptic plasticity — a mutual relationship. Phil. Trans. R. Soc. B 369, 20130515 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Woldemichael, B. T. & Mansuy, I. M. Micro-RNAs in cognition and cognitive disorders: potential for novel biomarkers and therapeutics. Biochem. Pharmacol. 104, 1–7 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Packer, A. N., Xing, Y., Harper, S. Q., Jones, L. & Davidson, B. L. The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease. J. Neurosci. 28, 14341–14346 (2008). This paper documents a reciprocal relationship between the regulatory factors REST and CoREST and the miRNAs miR-9 and miR-9* in the brains of mice with Huntington disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lusardi, T. A. et al. Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex. J. Cereb. Blood Flow Metab. 30, 744–756 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Hwang, J. Y., Kaneko, N., Noh, K. M., Pontarelli, F. & Zukin, R. S. The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J. Mol. Biol. 426, 3454–3466 (2014). This paper is the first to show that REST-dependent silencing of a miRNA is crucial for global ischaemia-induced neuronal death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Willert, J., Epping, M., Pollack, J. R., Brown, P. O. & Nusse, R. A transcriptional response to Wnt protein in human embryonic carcinoma cells. BMC. Dev. Biol. 2, 8 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Yu, M. et al. NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP. Neurobiol. Aging 34, 916–927 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. De Jager, P. L. et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat. Neurosci. 17, 1156–1163 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lunnon, K. et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat. Neurosci. 17, 1164–1170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chi, S. et al. Association of single-nucleotide polymorphism in ANK1 with late-onset Alzheimer's disease in Han Chinese. Mol. Neurobiol. 53, 6476–6481 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Birney, E., Smith, G. D. & Greally, J. M. Epigenome-wide association studies and the interpretation of disease -omics. PLoS. Genet. 12, e1006105 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Savas, J. N. et al. Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proc. Natl Acad. Sci. USA 105, 10820–10825 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Buckley, N. J., Johnson, R., Zuccato, C., Bithell, A. & Cattaneo, E. The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease. Neurobiol. Dis. 39, 28–39 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Conforti, P. et al. In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice. Gene Ther. 20, 678–685 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. von, S. M. et al. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nat. Neurosci. 19, 1321–1330 (2016).

    Article  CAS  Google Scholar 

  74. Wang, F. et al. Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease. Hum. Mol. Genet. 22, 3641–3653 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Mozaffarian, D. et al. Heart Disease and Stroke Statistics—2016 Update: a report from the American Heart Association. Circulation 133, e38–e60 (2016).

    PubMed  Google Scholar 

  76. Endres, M., Fan, G., Meisel, A., Dirnagl, U. & Jaenisch, R. Effects of cerebral ischemia in mice lacking DNA methyltransferase 1 in post-mitotic neurons. Neuroreport 12, 3763–3766 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Endres, M. et al. DNA methyltransferase contributes to delayed ischemic brain injury. J. Neurosci. 20, 3175–3181 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Annunziato, L., Pignataro, G. & Di Renzo, G. F. Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol. Rev. 56, 633–654 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Boscia, F. et al. Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions. J. Cereb. Blood Flow Metab. 26, 502–517 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Lanzillotta, A. et al. Targeted acetylation of NF-κB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window. Neurobiol. Dis. 49, 177–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Zhang, Z. G. & Chopp, M. Promoting brain remodeling to aid in stroke recovery. Trends Mol. Med. 21, 543–548 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu, X. S., Chopp, M., Zhang, R. L. & Zhang, Z. G. MicroRNAs in cerebral ischemia-induced neurogenesis. J. Neuropathol. Exp. Neurol. 72, 718–722 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Liu, X. S. et al. MicroRNA profiling in subventricular zone after stroke: miR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS ONE 6, e23461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liou, A. K., Clark, R. S., Henshall, D. C., Yin, X. M. & Chen, J. To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways. Prog. Neurobiol. 69, 103–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Moskowitz, M. A., Lo, E. H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ofengeim, D., Miyawaki, T. & Zukin, R. S. in Stroke: Pathophysiology, Diagnosis and Management 5th edn Ch. 6 (eds Mohr, J. P. et al.) 75–106 (Saunders, 2011).

    Book  Google Scholar 

  87. Siegel, G., Saba, R. & Schratt, G. MicroRNAs in neurons: manifold regulatory roles at the synapse. Curr. Opin. Genet. Dev. 21, 491–497 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Wong, H. K. et al. De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Hum. Mol. Genet. 22, 3077–3092 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Lagos, D. et al. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat. Cell Biol. 12, 513–519 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. DeWoskin, V. A. & Million, R. P. The epigenetics pipeline. Nat. Rev. Drug Discov. 12, 661–662 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Chuang, D. M., Leng, Y., Marinova, Z., Kim, H. J. & Chiu, C. T. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci. 32, 591–601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Falkenberg, K. J. et al. A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity. Cell Death Differ. 23, 1209–1218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kazantsev, A. G. & Thompson, L. M. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat. Rev. Drug Discov. 7, 854–868 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Green, K. N. et al. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J. Neurosci. 28, 11500–11510 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hathorn, T., Snyder-Keller, A. & Messer, A. Nicotinamide improves motor deficits and upregulates PGC- and BDNF gene expression in a mouse model of Huntington's disease. Neurobiol. Dis. 41, 43–50 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. d'Ydewalle, C., Bogaert, E. & Van Den Bosch, L. HDAC6 at the intersection of neuroprotection and neurodegeneration. Traffic 13, 771–779 (2012).

    Article  PubMed  CAS  Google Scholar 

  97. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Gardner, K. E., Allis, C. D. & Strahl, B. D. Operating on chromatin, a colorful language where context matters. J. Mol. Biol. 409, 36–46 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jakovcevski, M. & Akbarian, S. Epigenetic mechanisms in neurological disease. Nat. Med. 18, 1194–1204 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zovkic, I. B., Paulukaitis, B. S., Day, J. J., Etikala, D. M. & Sweatt, J. D. Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515, 582–586 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Maze, I. et al. Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87, 77–94 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci. 8, 355–367 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Grimes, J. A. et al. The co-repressor mSin3A is a functional component of the REST–CoREST repressor complex. J. Biol. Chem. 275, 9461–9467 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Naruse, Y., Aoki, T., Kojima, T. & Mori, N. Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Proc. Natl Acad. Sci. USA 96, 13691–13696 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Huang, Y., Myers, S. J. & Dingledine, R. Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat. Neurosci. 2, 867–872 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Zhang, Q., Piston, D. W. & Goodman, R. H. Regulation of corepressor function by nuclear NADH. Science 295, 1895–1897 (2002).

    CAS  PubMed  Google Scholar 

  110. Lee, M. G., Wynder, C., Cooch, N. & Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Shi, Y. J. Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19, 857–864 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Lunyak, V. V. et al. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747–1752 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Battaglioli, E. et al. REST repression of neuronal genes requires components of the hSWI.SNF complex. J. Biol. Chem. 277, 41038–41045 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Ooi, L., Belyaev, N. D., Miyake, K., Wood, I. C. & Buckley, N. J. BRG1 chromatin remodeling activity is required for efficient chromatin binding by repressor element 1-silencing transcription factor (REST) and facilitates REST-mediated repression. J. Biol. Chem. 281, 38974–38980 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Cheong, J. K. & Virshup, D. M. Casein kinase 1: complexity in the family. Int. J. Biochem. Cell Biol. 43, 465–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Chen, H. et al. DNA damage regulates UHRF1 stability via the SCF(β-TrCP) E3 ligase. Mol. Cell. Biol. 33, 1139–1148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nesti, E., Corson, G. M., McCleskey, M., Oyer, J. A. & Mandel, G. C-Terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation. Proc. Natl Acad. Sci. USA 111, E3929–E3936 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. McClelland, S. et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. eLife 3, e01267 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Johnson, D. S., Mortazavi, A., Myers, R. M. & Wold, B. Genome-wide mapping of in vivo protein–DNA interactions. Science 316, 1497–1502 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Abrajano, J. J. et al. Corepressor for element-1-silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions. Proc. Natl Acad. Sci. USA 107, 16685–16690 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mortazavi, A., Thompson, E. C., Garcia, S. T., Myers, R. M. & Wold, B. Comparative genomics modeling of the NRSF/REST repressor network: from single conserved sites to genome-wide repertoire. Genome Res. 16, 1208–1221 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wu, C. et al. A forebrain ischemic preconditioning model established in C57Black/Crj6 mice. J. Neurosci. Methods 107, 101–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Tanaka, H. et al. Ischemic preconditioning: neuronal survival in the face of caspase-3 activation. J. Neurosci. 24, 2750–2759 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Miyawaki, T. et al. Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons. Proc. Natl Acad. Sci. USA 105, 4892–4897 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Takada, Y. et al. Mammalian Polycomb Scmh1 mediates exclusion of Polycomb complexes from the XY body in the pachytene spermatocytes. Development 134, 579–590 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Lee, K. et al. Expression of Bmi-1 in epidermis enhances cell survival by altering cell cycle regulatory protein expression and inhibiting apoptosis. J. Invest. Dermatol. 128, 9–17 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Chatoo, W. et al. The Polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity. J. Neurosci. 29, 529–542 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lipinski, M. M. et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc. Natl Acad. Sci. USA 107, 14164–14169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zuccato, C. & Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 5, 311–322 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Shimojo, M. Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150Glued. J. Biol. Chem. 283, 34880–34886 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Dock, H., Theodorsson, A. & Theodorsson, E. DNA methylation inhibitor zebularine confers stroke protection in ischemic rats. Transl Stroke Res. 6, 296–300 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Kilgore, M. et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 35, 870–880 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Qing, H. et al. Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J. Exp. Med. 205, 2781–2789 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chiu, C. T., Liu, G., Leeds, P. & Chuang, D. M. Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington's disease. Neuropsychopharmacology 36, 2406–2421 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zadori, D., Geisz, A., Vamos, E., Vecsei, L. & Klivenyi, P. Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease. Pharmacol. Biochem. Behav. 94, 148–153 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Wang, Z., Leng, Y., Tsai, L. K., Leeds, P. & Chuang, D. M. Valproic acid attenuates blood–brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition. J. Cereb. Blood Flow Metab. 31, 52–57 (2011).

    Article  PubMed  CAS  Google Scholar 

  138. Liu, X. S. et al. Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience 220, 313–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Xuan, A. et al. Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sci. 90, 463–468 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Sadri-Vakili, G. et al. Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models. Hum. Mol. Genet. 16, 1293–1306 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Ricobaraza, A. et al. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model. Neuropsychopharmacology 34, 1721–1732 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. Ricobaraza, A., Cuadrado-Tejedor, M., Marco, S., Perez-Otano, I. & Garcia-Osta, A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22, 1040–1050 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Cuadrado-Tejedor, M., Ricobaraza, A. L., Torrijo, R., Franco, R. & Garcia-Osta, A. Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer's disease-like phenotype of a commonly used mouse model. Curr. Pharm. Des. 19, 5076–5084 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Giorgini, F. et al. Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J. Biol. Chem. 283, 7390–7400 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Hockly, E. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA 100, 2041–2046 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Faraco, G. et al. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol. Pharmacol. 70, 1876–1884 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Baltan, S., Bachleda, A., Morrison, R. S. & Murphy, S. P. Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia. Transl Stroke Res. 2, 411–423 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhang, Z. Y. & Schluesener, H. J. Oral administration of histone deacetylase inhibitor MS-275 ameliorates neuroinflammation and cerebral amyloidosis and improves behavior in a mouse model. J. Neuropathol. Exp. Neurol. 72, 178–185 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Dompierre, J. P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Yildirim, F. et al. Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury. Exp. Neurol. 210, 531–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516–519 (2007).

    Article  CAS  PubMed  Google Scholar 

  152. Luthi-Carter, R. et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc. Natl Acad. Sci. USA 107, 7927–7932 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Govindarajan, N., Agis-Balboa, R. C., Walter, J., Sananbenesi, F. & Fischer, A. Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression. J. Alzheimers Dis. 26, 187–197 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci. 23, 9418–9427 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kim, H. J., Leeds, P. & Chuang, D. M. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J. Neurochem. 110, 1226–1240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Cruz, J. C. & Tsai, L. H. A. Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr. Opin. Neurobiol. 14, 390–394 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge all the authors whose valuable work they could not include owing to the limited number of citations allowed. This work was supported by US National Institutes of Health grants NS046742, MH092877and HD083828; a generous grant from the F. M. Kirby Foundation and a National Alliance for Research on Schizophrenia and Depression (NARSAD) Distinguished Investigator Grant to R.S.Z.; and American Heart Association Scientist Development Grant 16SDG31500001 and NARSAD Young Investigator Grant 25369 to J.-Y.H. R.S.Z. is the F. M. Kirby Chair in Neural Repair and Protection.

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Glossary

Histone post-translational modifications

Covalent modifications of histone proteins, including methylation, phosphorylation, acetylation, ubiquitylation and sumoylation.

Nucleosome

The basic building unit of chromatin. It comprises 147 bp of DNA wrapped around a histone octamer that contains two molecules of each of the four histones H2A, H2B, H3 and H4.

Long-term potentiation

(LTP). A long-lasting (hours or days) increase in the response of neurons to the stimulation of their afferents following a brief patterned stimulus (for example, a 100 Hz stimulus).

Contextual fear conditioning

A form of conditioning in which animals associate the conditioning context (the 'neutral' conditioned stimulus) with an aversive stimulus (for example, a footshock).

Oxidative stress

A disturbance in the pro-oxidant–antioxidant balance in favour of the former, which can lead to cellular damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products and lipid peroxidation products.

Ubiquitin-based proteasomal degradation

A process that is initiated by a protein complex and is based on ubiquitin, a 76-amino acid protein that forms a covalent link with (and thereby marks) proteins destined for degradation. Proteins tagged by a poly-ubiquitin chain are targeted to the proteasome, which is a large, multimeric, barrel-like complex that degrades proteins by proteolysis.

Single-nucleotide polymorphisms

(SNPs). A type of genetic variation within a DNA sequence that occurs when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (for example, cytosine).

RNA-induced silencing complexes

(RISCs). A complex of proteins that is involved in silencing target mRNAs.

Ingenuity Pathway Analysis

A web-based software application that enables the analysis, integration and understanding of data from gene expression, microRNA, and single-nucleotide polymorphism microarrays; and metabolomics, proteomics and RNA sequencing experiments.

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Hwang, JY., Aromolaran, K. & Zukin, R. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 18, 347–361 (2017). https://doi.org/10.1038/nrn.2017.46

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