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Histone deacetylase 4 (HDAC4): a new player in anorexia nervosa?

Molecular Psychiatry volume 24, pages 1425–1434 (2019)Cite this article

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Abstract

Anorexia nervosa (AN) and other eating disorders continue to constitute significant challenges for individual and public health. AN is thought to develop as a result of complex interactions between environmental triggers, psychological risk factors, sociocultural influences, and genetic vulnerability. Recent research developments have highlighted a novel potentially relevant component in the AN etiology—activity of the histone deacetylase 4 (HDAC4) gene that has emerged in several recent studies related to AN. HDAC4 is a member of the ubiquitously important family of epigenetic modifier enzymes called histone deacetylases and has been implicated in processes related to the formation and function of the central nervous system (CNS), bone, muscle, and metabolism. In a family affected by eating disorders, a missense mutation in HDAC4 (A786T) was found to segregate with the illness. The relevance of this mutation in eating-related behaviors was further confirmed with mouse models. Despite  the fact that HDAC4 has not been identified as a significant signal in genome-wide association studies in AN, several studies have found significant or near-significant methylation differences in HDAC4 locus in peripheral tissues of actively ill AN patients in comparison with different control groups. Limitations of these studies include a lack of understanding of to what extent the changes in methylation are predictive of AN as such changes might also occur as a consequence of the disease. It remains to be determined how methylation in peripheral tissues correlates with that in the CNS and how different methylation patterns affect HDAC4 expression. The present review discusses the findings and potential roles of HDAC4 in AN. Its emerging roles in learning and neuroplasticity may be specific and relevant for the etiology of AN and potentially lead to novel therapeutic approaches.

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References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Association, Washington, DC: DSM-5; 2013.

    Book  Google Scholar 

  2. Sweeting H, Walker L, MacLean A, Patterson C, Raisanen U, Hunt K. Prevalence of eating disorders in males: a review of rates reported in academic research and UK mass media. Int J Mens Health. 2015;14:86–112.

    Google Scholar 

  3. Hudson JI, Hiripi E, Pope HG Jr., Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61:348–58.

    Article  PubMed  Google Scholar 

  4. Eddy KT, Tabri N, Thomas JJ, Murray HB, Keshaviah A, Hastings E, et al. Recovery from anorexia nervosa and bulimia nervosa at 22-year follow-up. J Clin Psychiatry. 2017;78:184–9.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fichter MM, Quadflieg N, Crosby RD, Koch S. Long-term outcome of anorexia nervosa: Results from a large clinical longitudinal study. Int J Eat Disord. 2017;50:1018–30.

    Article  PubMed  Google Scholar 

  6. Yilmaz Z, Hardaway JA, Bulik CM. Genetics and epigenetics of eating disorders. Adv Genom Genet. 2015;5:131–50.

    CAS  Google Scholar 

  7. Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL. Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry. 2006;63:305–12.

    Article  PubMed  Google Scholar 

  8. Baker JH, Schaumberg K, Munn-Chernoff MA. Genetics of anorexia nervosa. Curr Psychiatry Rep. 2017;19:84.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh PR, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Duncan L, Yilmaz Z, Gaspar H, Walters R, Goldstein J, Anttila V, et al. Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. Am J Psychiatry. 2017;174:850–8.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Huckins LM, Hatzikotoulas K, Southam L, Thornton LM, Steinberg J, Aguilera-McKay F, et al. Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. Mol Psychiatry. 2018;23:1169–80.

    Article  CAS  PubMed  Google Scholar 

  12. Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ, et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry. 2011;16:949–59.

    Article  CAS  PubMed  Google Scholar 

  13. Boraska V, Franklin CS, Floyd JA, Thornton LM, Huckins LM, Southam L, et al. A genome-wide association study of anorexia nervosa. Mol Psychiatry. 2014;19:1085–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nestler EJ, Pena CJ, Kundakovic M, Mitchell A, Akbarian S. Epigenetic basis of mental illness. Neuroscientist. 2016;22:447–63.

    Article  CAS  PubMed  Google Scholar 

  15. Szyf M. Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications. Eur Neuropsychopharmacol. 2015;25:682–702.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang G, Pradhan S. Mammalian epigenetic mechanisms. IUBMB Life. 2014;66:240–56.

    Article  CAS  PubMed  Google Scholar 

  17. Thaler L, Steiger H. Eating disorders and epigenetics. Adv Exp Med Biol. 2017;978:93–103.

    Article  CAS  PubMed  Google Scholar 

  18. Hubel C, Marzi SJ, Breen G, Bulik CM. Epigenetics in eating disorders: a systematic review. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0254-7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Frieling H, Romer KD, Scholz S, Mittelbach F, Wilhelm J, De Zwaan M, et al. Epigenetic dysregulation of dopaminergic genes in eating disorders. Int J Eat Disord. 2010;43:577–83.

    Article  PubMed  Google Scholar 

  20. Frieling H, Gozner A, Romer KD, Lenz B, Bonsch D, Wilhelm J, et al. Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry. 2007;12:229–30.

    Article  CAS  PubMed  Google Scholar 

  21. Kim YR, Kim JH, Kim MJ, Treasure J. Differential methylation of the oxytocin receptor gene in patients with anorexia nervosa: a pilot study. PLoS ONE. 2014;9:e88673.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kesselmeier M, Putter C, Volckmar AL, Baurecht H, Grallert H, Illig T, et al. High-throughput DNA methylation analysis in anorexia nervosa confirms TNXB hypermethylation. World J Biol Psychiatry. 2018;19:187–99.

    Article  PubMed  Google Scholar 

  23. Booij L, Casey KF, Antunes JM, Szyf M, Joober R, Israel M, et al. DNA methylation in individuals with anorexia nervosa and in matched normal-eater controls: A genome-wide study. Int J Eat Disord. 2015;48:874–82.

    Article  PubMed  Google Scholar 

  24. Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007;76:75–100.

    Article  CAS  PubMed  Google Scholar 

  25. Eberharter A, Becker PB. Histone acetylation: a switch between repressive and permissive chromatin. Second Rev Ser chromatin Dyn EMBO Rep. 2002;3:224–9.

    CAS  Google Scholar 

  26. Kurdistani SK, Tavazoie S, Grunstein M. Mapping global histone acetylation patterns to gene expression. Cell. 2004;117:721–33.

    Article  CAS  PubMed  Google Scholar 

  27. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10:32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–49.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tang B, Dean B, Thomas EA. Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. Transl Psychiatry. 2011;1:e64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hobara T, Uchida S, Otsuki K, Matsubara T, Funato H, Matsuo K, et al. Altered gene expression of histone deacetylases in mood disorder patients. J Psychiatr Res. 2010;44:263–70.

    Article  PubMed  Google Scholar 

  31. Morris MJ, Monteggia LM. Unique functional roles for class I and class II histone deacetylases in central nervous system development and function. Int J Dev Neurosci. 2013;31:370–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cui H, Moore J, Ashimi SS, Mason BL, Drawbridge JN, Han S, et al. Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. J Clin Invest. 2013;123:4706–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lutter M, Khan MZ, Satio K, Davis KC, Kidder IJ, McDaniel L, et al. The eating-disorder associated HDAC4A778T mutation alters feeding behaviors in female mice. Biol Psychiatry. 2017;81:770–7.

    Article  CAS  PubMed  Google Scholar 

  34. Subramanian S, Braun PR, Han S, Potash JB. Investigation of differential HDAC4 methylation patterns in eating disorders. Psychiatr Genet. 2018;28:12–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Steiger H, Booij L, Kahan E, McGregor K, Thaler L, Fletcher E, et al. A longitudinal, epigenomewide study of DNA methylation in Anorexia Nervosa: Results in actively ill, partially weight restored, long-term remitted, and non-eating-disordered women. J Psychiatry Neurosci. 2019;44:1–9.

    Article  Google Scholar 

  36. Zhang DE, Nelson DA. Histone acetylation in chicken erythrocytes. Rates of acetylation and evidence that histones in both active and potentially active chromatin are rapidly modified. Biochem J. 1988;250:233–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol. 2002;3:643–51.

    Article  CAS  PubMed  Google Scholar 

  38. Authement ME, Kodangattil JN, Gouty S, Rusnak M, Symes AJ, Cox BM, et al. Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling. Neuron. 2015;86:1240–52.

    Article  CAS  PubMed  Google Scholar 

  39. Clayton AL, Hazzalin CA, Mahadevan LC. Enhanced histone acetylation and transcription: a dynamic perspective. Mol Cell. 2006;23:289–96.

    Article  CAS  PubMed  Google Scholar 

  40. Fink DS, Galea S. Life course epidemiology of trauma and related psychopathology in civilian populations. Curr Psychiatry Rep. 2015;17:31.

    Article  PubMed  Google Scholar 

  41. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–54.

    Article  CAS  PubMed  Google Scholar 

  42. Benoit JD, Rakic P, Frick KM. Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res. 2015;281:1–8.

    Article  CAS  PubMed  Google Scholar 

  43. Zhang TY, Hellstrom IC, Bagot RC, Wen X, Diorio J, Meaney MJ. Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. J Neurosci. 2010;30:13130–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Reus GZ, Abelaira HM, dos Santos MA, Carlessi AS, Tomaz DB, Neotti MV, et al. Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors. Behav Brain Res. 2013;256:451–6.

    Article  CAS  PubMed  Google Scholar 

  45. Curran E, Adamson G, Rosato M, De Cock P, Leavey G. Profiles of childhood trauma and psychopathology: US National Epidemiologic Survey. Soc Psychiatry Psychiatr Epidemiol. 2018;53:1207–19.

    Article  PubMed  Google Scholar 

  46. Weaver IC. Epigenetic effects of glucocorticoids. Semin Fetal Neonatal Med. 2009;14:143–50.

    Article  PubMed  Google Scholar 

  47. Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S. Use of epigenetic drugs in disease: an overview. Genet Epigenet. 2014;6:9–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ganguly S, Seth S. A translational perspective on histone acetylation modulators in psychiatric disorders. Psychopharmacology. 2018;235:1867–73.

    Article  CAS  PubMed  Google Scholar 

  49. Kramer OH, Gottlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab. 2001;12:294–300.

    Article  CAS  PubMed  Google Scholar 

  50. Dokmanovic M, Marks PA. Prospects: histone deacetylase inhibitors. J Cell Biochem. 2005;96:293–304.

    Article  CAS  PubMed  Google Scholar 

  51. Zwergel C, Valente S, Jacob C, Mai A. Emerging approaches for histone deacetylase inhibitor drug discovery. Expert Opin Drug Discov. 2015;10:599–613.

    Article  CAS  PubMed  Google Scholar 

  52. Choong CJ, Sasaki T, Hayakawa H, Yasuda T, Baba K, Hirata Y, et al. A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson’s disease. Neurobiol Aging. 2016;37:103–16.

    Article  CAS  PubMed  Google Scholar 

  53. Qiu X, Xiao X, Li N, Li Y. Histone deacetylases inhibitors (HDACis) as novel therapeutic application in various clinical diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2017;72:60–72.

    Article  CAS  PubMed  Google Scholar 

  54. Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol. 2006;13:563–7.

    Article  CAS  PubMed  Google Scholar 

  55. Harwood AJ. Neurodevelopment and mood stabilizers. Curr Mol Med. 2003;3:472–82.

    Article  CAS  PubMed  Google Scholar 

  56. Kinrys G, Pollack MH, Simon NM, Worthington JJ, Nardi AE, Versiani M. Valproic acid for the treatment of social anxiety disorder. Int Clin Psychopharmacol. 2003;18:169–72.

    PubMed  Google Scholar 

  57. Mahgoub M, Monteggia LM. Epigenetics and psychiatry. Neurotherapeutics. 2013;10:734–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fuchikami M, Yamamoto S, Morinobu S, Okada S, Yamawaki Y, Yamawaki S. The potential use of histone deacetylase inhibitors in the treatment of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:320–4.

    Article  CAS  PubMed  Google Scholar 

  59. Jurkin J, Zupkovitz G, Lagger S, Grausenburger R, Hagelkruys A, Kenner L, et al. Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. Cell Cycle. 2011;10:406–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HW, Mastroeni D, et al. The epigenetics of aging and neurodegeneration. Prog Neurobiol. 2015;131:21–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Peng L, Seto E. Deacetylation of nonhistone proteins by HDACs and the implications in cancer. Handb Exp Pharmacol. 2011;206:39–56.

    Article  CAS  PubMed  Google Scholar 

  62. Parra M. Class IIa HDACs-new insights into their functions in physiology and pathology. FEBS J. 2015;282:1736–44.

    Article  CAS  PubMed  Google Scholar 

  63. Lahm A, Paolini C, Pallaoro M, Nardi MC, Jones P, Neddermann P, et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci USA. 2007;104:17335–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez JG, et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell. 2011;145:607–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, et al. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell. 2002;9:45–57.

    Article  CAS  PubMed  Google Scholar 

  66. Bolger TA, Yao TP. Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. J Neurosci. 2005;25:9544–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Verdin E, Dequiedt F, Kasler HG. Class II histone deacetylases: versatile regulators. Trends Genet. 2003;19:286–93.

    Article  CAS  PubMed  Google Scholar 

  68. Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J Neurochem. 2003;85:151–9.

    Article  CAS  PubMed  Google Scholar 

  69. Mielcarek M, Zielonka D, Carnemolla A, Marcinkowski JT, Guidez F. HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements. Front Cell Neurosci. 2015;9:42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Sando R 3rd, Gounko N, Pieraut S, Liao L, Yates J 3rd, Maximov A. HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell. 2012;151:821–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Grozinger CM, Hassig CA, Schreiber SL. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci USA. 1999;96:4868–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Di Giorgio E, Brancolini C. Regulation of class IIa HDAC activities: it is not only matter of subcellular localization. Epigenomics. 2016;8:251–69.

    Article  PubMed  CAS  Google Scholar 

  73. Martin M, Kettmann R, Dequiedt F. Class IIa histone deacetylases: conducting development and differentiation. Int J Dev Biol. 2009;53:291–301.

    Article  CAS  PubMed  Google Scholar 

  74. Makinistoglu MP, Karsenty G. The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts. Mol Metab. 2015;4:64–9.

    Article  CAS  PubMed  Google Scholar 

  75. Benton MC, Johnstone A, Eccles D, Harmon B, Hayes MT, Lea RA, et al. An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss. Genome Biol. 2015;16:8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron. 2005;48:303–14.

    Article  CAS  PubMed  Google Scholar 

  77. Majdzadeh N, Wang L, Morrison BE, Bassel-Duby R, Olson EN, D’Mello SR. HDAC4 inhibits cell-cycle progression and protects neurons from cell death. Dev Neurobiol. 2008;68:1076–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell. 2004;119:555–66.

    Article  CAS  PubMed  Google Scholar 

  79. Miska EA, Langley E, Wolf D, Karlsson C, Pines J, Kouzarides T. Differential localization of HDAC4 orchestrates muscle differentiation. Nucl Acids Res. 2001;29:3439–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen B, Cepko CL. HDAC4 regulates neuronal survival in normal and diseased retinas. Science. 2009;323:256–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Blixt NC, Faulkner BK, Astleford K, Lelich R, Schering J, Spencer E, et al. Class II and IV HDACs function as inhibitors of osteoclast differentiation. PLoS ONE. 2017;12:e0185441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science. 2009;326:1549–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Li J, Chen J, Ricupero CL, Hart RP, Schwartz MS, Kusnecov A, et al. Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nat Med. 2012;18:783–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Darcy MJ, Calvin K, Cavnar K, Ouimet CC. Regional and subcellular distribution of HDAC4 in mouse brain. J Comp Neurol. 2010;518:722–40.

    Article  CAS  PubMed  Google Scholar 

  85. Takase K, Oda S, Kuroda M, Funato H. Monoaminergic and neuropeptidergic neurons have distinct expression profiles of histone deacetylases. PLoS ONE. 2013;8:e58473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Price V, Wang L, D’Mello SR. Conditional deletion of histone deacetylase-4 in the central nervous system has no major effect on brain architecture or neuronal viability. J Neurosci Res. 2013;91:407–15.

    Article  CAS  PubMed  Google Scholar 

  87. Kim MS, Akhtar MW, Adachi M, Mahgoub M, Bassel-Duby R, Kavalali ET, et al. An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J Neurosci. 2012;32:10879–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Fitzsimons HL, Schwartz S, Given FM, Scott MJ. The histone deacetylase HDAC4 regulates long-term memory in Drosophila. PLoS ONE. 2013;8:e83903.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, McLeod DR, et al. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010;87:219–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wheeler PG, Huang D, Dai Z. Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals. Am J Med Genet A. 2014;164A:1826–9.

    Article  PubMed  CAS  Google Scholar 

  91. Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nardone S, Sams DS, Reuveni E, Getselter D, Oron O, Karpuj M, et al. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry. 2014;4:1–9.

    Article  CAS  Google Scholar 

  93. Shen X, Chen J, Li J, Kofler J, Herrup K. Neurons in vulnerable regions of the Alzheimer’s disease brain display reduced ATM signaling. eNeuro. 2016;3:1–18.

    Article  Google Scholar 

  94. Herrup K, Li J, Chen J. The role of ATM and DNA damage in neurons: upstream and downstream connections. DNA Repair (Amst). 2013;12:600–4.

    Article  CAS  Google Scholar 

  95. Penrod RD, Carreira MB, Taniguchi M, Kumar J, Maddox SA, Cowan CW. Novel role and regulation of HDAC4 in cocaine-related behaviors. Addict Biol. 2018;23:653–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Torres OV, Ladenheim B, Jayanthi S, McCoy MT, Krasnova IN, Vautier FA, et al. An acute methamphetamine injection downregulates the expression of several histone deacetylases (HDACs) in the mouse nucleus accumbens: potential regulatory role of HDAC2 expression. Neurotox Res. 2016;30:32–40.

    Article  CAS  PubMed  Google Scholar 

  97. Griffin EA Jr., Melas PA, Zhou R, Li Y, Mercado P, et al. Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5. Sci Adv. 2017;3:1–13.

    Article  CAS  Google Scholar 

  98. Wang L, Lv Z, Hu Z, Sheng J, Hui B, Sun J, et al. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement. Neuropsychopharmacology. 2010;35:913–28.

    Article  CAS  PubMed  Google Scholar 

  99. Wang WH, Cheng LC, Pan FY, Xue B, Wang DY, Chen Z, et al. Intracellular trafficking of histone deacetylase 4 regulates long-term memory formation. Anat Rec (Hoboken). 2011;294:1025–34.

    Article  CAS  Google Scholar 

  100. Mathias RA, Guise AJ, Cristea IM. Post-translational modifications regulate class IIa histone deacetylase (HDAC) function in health and disease. Mol Cell Proteom. 2015;14:456–70.

    Article  CAS  Google Scholar 

  101. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110:479–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang AH, Yang XJ. Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Mol Cell Biol. 2001;21:5992–6005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sailaja BS, Cohen-Carmon D, Zimmerman G, Soreq H, Meshorer E. Stress-induced epigenetic transcriptional memory of acetylcholinesterase by HDAC4. Proc Natl Acad Sci USA. 2012;109:E3687–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Fitzsimons HL. The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart? Neurobiol Learn Mem. 2015;123:149–58.

    Article  CAS  PubMed  Google Scholar 

  105. Zhang P, Sun Q, Zhao C, Ling S, Li Q, Chang YZ, et al. HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4. Cell Signal. 2014;26:556–63.

    Article  CAS  PubMed  Google Scholar 

  106. Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T, Inuabasi L, et al. HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol. 2013;11:e1001717.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Obri A, Khrimian L, Karsenty G, Oury F. Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol. 2018;14:174–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell. 2013;155:228–41.

    Article  CAS  PubMed  Google Scholar 

  109. Wu Y, Hou F, Wang X, Kong Q, Han X, Bai B. Aberrant expression of histone deacetylases 4 in cognitive disorders: Molecular mechanisms and a potential target. Front Mol Neurosci. 2016;9:114.

    PubMed  PubMed Central  Google Scholar 

  110. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2010;35:870–80.

    Article  CAS  PubMed  Google Scholar 

  111. Sharma RP, Grayson DR, Gavin DP. Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the National Brain Databank microarray collection. Schizophr Res. 2008;98:111–7.

    Article  PubMed  Google Scholar 

  112. Sarkar A, Chachra P, Kennedy P, Pena CJ, Desouza LA, Nestler EJ, et al. Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior. Neuropsychopharmacology. 2014;39:2221–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541:81–6.

    Article  CAS  PubMed  Google Scholar 

  115. Abu-Farha M, Tiss A, Abubaker J, Khadir A, Al-Ghimlas F, Al-Khairi I, et al. Proteomics analysis of human obesity reveals the epigenetic factor HDAC4 as a potential target for obesity. PLoS ONE. 2013;8:e75342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ronn T, Volkov P, Davegardh C, Dayeh T, Hall E, Olsson AH, et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet. 2013;9:1–16.

    Article  CAS  Google Scholar 

  117. Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum Mol Genet. 2018;27:3641–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hinney A, Kesselmeier M, Jall S, Volckmar AL, Focker M, Antel J, et al. Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. Mol Psychiatry. 2017;22:321–2.

    Article  CAS  PubMed  Google Scholar 

  119. Maddox SA, Kilaru V, Shin J, Jovanovic T, Almli LM, Dias BG, et al. Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. Mol Psychiatry. 2018;23:658–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Sundgot-Borgen J. Risk and trigger factors for the development of eating disorders in female elite athletes. Med Sci Sports Exerc. 1994;26:414–9.

    Article  CAS  PubMed  Google Scholar 

  121. Clocchiatti A, Di Giorgio E, Demarchi F, Brancolini C. Beside the MEF2 axis: unconventional functions of HDAC4. Cell Signal. 2013;25:269–76.

    Article  CAS  PubMed  Google Scholar 

  122. Booij L, Greenlaw K, Kahan E, McGregor K, Thaler L, Labbe A, et al. The role of DNA methylation of the histone deacetylase 4 (HDAC4) gene in Anorexia Nervosa. International Conference on Eating Disorders, Academy of Eating Disorders. New York, NY; 2019.

  123. Di Sante J, Ismaylova E, Nemoda Z, Gouin J-P, Yu WJ, Caldwell W, et al. Peripheral DNA methylation of HPA axis-related genes in humans: Cross-tissue convergence, two-year stability and behavioural and neural correlates. Psychoneuroendocrinology. 2018;97:196–205.

    Article  PubMed  CAS  Google Scholar 

  124. Aronica L, Levine AJ, Brennan K, Mi J, Gardner C, Haile RW, et al. A systematic review of studies of DNA methylation in the context of a weight loss intervention. Epigenomics. 2017;9:769–87.

    Article  CAS  PubMed  Google Scholar 

  125. Baker JH, Girdler SS, Bulik CM. The role of reproductive hormones in the development and maintenance of eating disorders. Expert Rev Obstet Gynecol. 2012;7:573–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tremblay BL, Guenard F, Rudkowska I, Lemieux S, Couture P, Vohl MC. Epigenetic changes in blood leukocytes following an omega-3 fatty acid supplementation. Clin Epigenetics. 2017;9:43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Leong H, Sloan JR, Nash PD, Greene GL. Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha. Mol Endocrinol. 2005;19:2930–42.

    Article  CAS  PubMed  Google Scholar 

  128. Vanacker JM, Pettersson K, Gustafsson JA, Laudet V. Transcriptional targets shared by estrogen receptor- related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta. EMBO J. 1999;18:4270–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Stein RA, McDonnell DP. Estrogen-related receptor alpha as a therapeutic target in cancer. Endocr Relat Cancer. 2006;13(Suppl 1):S25–32.

    Article  CAS  PubMed  Google Scholar 

  130. Cao X, Xu P, Oyola MG, Xia Y, Yan X, Saito K, et al. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. J Clin Invest. 2014;124:4351–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yao YL, Yang WM. Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their nonhistone substrates. J Biomed Biotechnol. 2011;2011:146493.

    Article  PubMed  CAS  Google Scholar 

  132. Bassett SA, Barnett MP. The role of dietary histone deacetylases (HDACs) inhibitors in health and disease. Nutrients. 2014;6:4273–301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Kidd A, Steinglass J. What can cognitive neuroscience teach us about anorexia nervosa? Curr Psychiatry Rep. 2012;14:415–20.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Tchanturia K, Harrison A, Davies H, Roberts M, Oldershaw A, Nakazato M, et al. Cognitive flexibility and clinical severity in eating disorders. PLoS ONE. 2011;6:e20462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Abbate-Daga G, Amianto F, Delsedime N, De-Bacco C, Fassino S. Resistance to treatment and change in anorexia nervosa [corrected]: a clinical overview. BMC Psychiatry. 2013;13:294.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Schmauss C. The roles of class I histone deacetylases (HDACs) in memory, learning, and executive cognitive functions: A review. Neurosci Biobehav Rev. 2017;83:63–71.

    Article  CAS  PubMed  Google Scholar 

  137. Mahgoub M, Monteggia LM. A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory. Learn Mem. 2014;21:564–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Keel PK, Dorer DJ, Franko DL, Jackson SC, Herzog DB. Postremission predictors of relapse in women with eating disorders. Am J Psychiatry. 2005;162:2263–8.

    Article  PubMed  Google Scholar 

  139. Troop NA, Treasure JL. Psychosocial factors in the onset of eating disorders: responses to life-events and difficulties. Br J Med Psychol. 1997;70(Pt 4):373–85.

    Article  PubMed  Google Scholar 

  140. Adler SM, Schmauss C. Cognitive deficits triggered by early life stress: The role of histone deacetylase 1. Neurobiol Dis. 2016;94:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wey HY, Gilbert TM, Zurcher NR, She A, Bhanot A, Taillon BD, et al. Insights into neuroepigenetics through human histone deacetylase PET imaging. Sci Transl Med. 2016;8:1–10.

    Article  CAS  Google Scholar 

  142. Sild M, Chiarella J, Casey KF, Massarweh G, Soucy J-P, Leyton M, et al. The impact of childhood trauma on in vivo brain measures of histone deacetylases in adulthood: A pilot study. Annual meeting of the Canadian College of Neuropsychopharmacology. Vancouver, Canada; 2018.

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Acknowledgements

We thank Keelin Greenlaw, M.Sc, for contributing supplementary materials to this manuscript. Dr. Linda Booij was supported by a New Investigator Award from the Canadian Institutes of Health Research and a NARSAD Independent Investigator Award from the Brain & Behavior Research Foundation. Dr. Mari Sild was supported by a Concordia University Horizon Postdoctoral Fellowship.

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  1. Department of Psychology, Concordia University, Montreal, QC, Canada

    Mari Sild & Linda Booij

  2. CHU Sainte-Justine Hospital Research Center, Montreal, QC, Canada

    Mari Sild & Linda Booij

  3. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Linda Booij

  4. Department of Psychiatry, University of Montreal, Montreal, QC, Canada

    Linda Booij

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  1. Mari Sild
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Sild, M., Booij, L. Histone deacetylase 4 (HDAC4): a new player in anorexia nervosa?. Mol Psychiatry 24, 1425–1434 (2019). https://doi.org/10.1038/s41380-019-0366-8

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