Advertisement

Chromodomain Y-like Protein–Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors

  • Author Footnotes
    1 YL and ML contributed equally to this work.
    Yongqing Liu
    Footnotes
    1 YL and ML contributed equally to this work.
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 YL and ML contributed equally to this work.
    Minghua Li
    Footnotes
    1 YL and ML contributed equally to this work.
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Minghua Fan
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Yan Song
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Huajing Yu
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
    Search for articles by this author
  • Xiaojie Zhi
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Kuo Xiao
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Shirong Lai
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Jingliang Zhang
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Xueqin Jin
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China
    Search for articles by this author
  • Yongfeng Shang
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
    Search for articles by this author
  • Jing Liang
    Correspondence
    Address correspondence to Jing Liang, Ph.D., Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xue Yuan Road, Beijing 100191, China.
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
    Search for articles by this author
  • Zhuo Huang
    Correspondence
    Zhuo Huang, Ph.D., Department of Molecular and Cellular Pharmacology, Peking University Health Science Center, 38 Xue Yuan Road, Beijing 100191, China.
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China

    Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 YL and ML contributed equally to this work.
Published:December 05, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.11.025

      Abstract

      Background

      Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process.

      Methods

      We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification.

      Results

      The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress–induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter.

      Conclusions

      Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Koretz D.
        • Merikangas K.R.
        • et al.
        The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R).
        JAMA. 2003; 289: 3095-3105
        • Krishnan V.
        • Nestler E.J.
        The molecular neurobiology of depression.
        Nature. 2008; 455: 894-902
        • Russo S.J.
        • Nestler E.J.
        The brain reward circuitry in mood disorders.
        Nat Rev Neurosci. 2013; 14: 609-625
        • Nestler E.J.
        • Pena C.J.
        • Kundakovic M.
        • Mitchell A.
        • Akbarian S.
        Epigenetic basis of mental illness.
        Neuroscientist. 2016; 22: 447-463
        • Nestler E.J.
        Epigenetic mechanisms of depression.
        JAMA Psychiatry. 2014; 71: 454-456
        • Chen Y.
        • Sprung R.
        • Tang Y.
        • Ball H.
        • Sangras B.
        • Kim S.C.
        • et al.
        Lysine propionylation and butyrylation are novel post-translational modifications in histones.
        Mol Cell Proteomics. 2007; 6: 812-819
        • Peng C.
        • Lu Z.
        • Xie Z.
        • Cheng Z.
        • Chen Y.
        • Tan M.
        • et al.
        The first identification of lysine malonylation substrates and its regulatory enzyme.
        Mol Cell Proteomics. 2011; 10M111.012658
        • Tan M.
        • Luo H.
        • Lee S.
        • Jin F.
        • Yang J.S.
        • Montellier E.
        • et al.
        Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification.
        Cell. 2011; 146: 1016-1028
        • Dai L.
        • Peng C.
        • Montellier E.
        • Lu Z.
        • Chen Y.
        • Ishii H.
        • et al.
        Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark.
        Nat Chem Biol. 2014; 10: 365-370
        • Xie Z.
        • Zhang D.
        • Chung D.
        • Tang Z.
        • Huang H.
        • Dai L.
        • et al.
        Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation.
        Mol Cell. 2016; 62: 194-206
        • Sabari B.R.
        • Tang Z.
        • Huang H.
        • Yong-Gonzalez V.
        • Molina H.
        • Kong H.E.
        • et al.
        Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation.
        Mol Cell. 2015; 58: 203-215
        • Bao X.
        • Wang Y.
        • Li X.
        • Li X.M.
        • Liu Z.
        • Yang T.
        • et al.
        Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach.
        Elife. 2014; 3: 02999
        • Feldman J.L.
        • Baeza J.
        • Denu J.M.
        Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins.
        J Biol Chem. 2013; 288: 31350-31356
        • Fellows R.
        • Denizot J.
        • Stellato C.
        • Cuomo A.
        • Jain P.
        • Stoyanova E.
        • et al.
        Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases.
        Nat Commun. 2018; 9: 105
        • Zhao D.
        • Guan H.
        • Zhao S.
        • Mi W.
        • Wen H.
        • Li Y.
        • et al.
        YEATS2 is a selective histone crotonylation reader.
        Cell Res. 2016; 26: 629-632
        • Li Y.
        • Sabari B.R.
        • Panchenko T.
        • Wen H.
        • Zhao D.
        • Guan H.
        • et al.
        Molecular coupling of histone crotonylation and active transcription by AF9 YEATS domain.
        Mol Cell. 2016; 62: 181-193
        • Zhang Y.
        • Yang X.
        • Gui B.
        • Xie G.
        • Zhang D.
        • Shang Y.
        • et al.
        Corepressor protein CDYL functions as a molecular bridge between polycomb repressor complex 2 and repressive chromatin mark trimethylated histone lysine 27.
        J Biol Chem. 2011; 286: 42414-42425
        • Qi C.
        • Liu S.
        • Qin R.
        • Zhang Y.
        • Wang G.
        • Shang Y.
        • et al.
        Coordinated regulation of dendrite arborization by epigenetic factors CDYL and EZH2.
        J Neurosci. 2014; 34: 4494-4508
        • Li X.
        • Liang J.
        • Yu H.
        • Su B.
        • Xiao C.
        • Shang Y.
        • et al.
        Functional consequences of new exon acquisition in mammalian chromodomain Y-like (CDYL) genes.
        Trends Genet. 2007; 23: 427-431
        • Liu Y.
        • Lai S.
        • Ma W.
        • Ke W.
        • Zhang C.
        • Liu S.
        • et al.
        CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression.
        Nat Commun. 2017; 8: 355
        • Liu S.
        • Yu H.
        • Liu Y.
        • Liu X.
        • Zhang Y.
        • Bu C.
        • et al.
        Chromodomain protein CDYL acts as a crotonyl-CoA hydratase to regulate histone crotonylation and spermatogenesis.
        Mol Cell. 2017; 67: 853-866 e855
        • Golden S.A.
        • Covington 3rd, H.E.
        • Berton O.
        • Russo S.J.
        A standardized protocol for repeated social defeat stress in mice.
        Nat Protoc. 2011; 6: 1183-1191
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Golden S.A.
        • Christoffel D.J.
        • Heshmati M.
        • Hodes G.E.
        • Magida J.
        • Davis K.
        • et al.
        Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression.
        Nat Med. 2013; 19: 337-344
        • Ota K.T.
        • Liu R.J.
        • Voleti B.
        • Maldonado-Aviles J.G.
        • Duric V.
        • Iwata M.
        • et al.
        REDD1 is essential for stress-induced synaptic loss and depressive behavior.
        Nat Med. 2014; 20: 531-535
        • Kim C.S.
        • Brager D.H.
        • Johnston D.
        Perisomatic changes in h-channels regulate depressive behaviors following chronic unpredictable stress.
        Mol Psychiatry. 2018; 23: 892-903
        • Liu Y.
        • Liu S.
        • Yuan S.
        • Yu H.
        • Zhang Y.
        • Yang X.
        • et al.
        Chromodomain protein CDYL is required for transmission/restoration of repressive histone marks.
        J Mol Cell Biol. 2017; 9: 178-194
        • Carlen M.
        What constitutes the prefrontal cortex?.
        Science. 2017; 358: 478-482
        • Kang H.J.
        • Voleti B.
        • Hajszan T.
        • Rajkowska G.
        • Stockmeier C.A.
        • Licznerski P.
        • et al.
        Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.
        Nat Med. 2012; 18: 1413-1417
        • Wohleb E.S.
        • Franklin T.
        • Iwata M.
        • Duman R.S.
        Integrating neuroimmune systems in the neurobiology of depression.
        Nat Rev Neurosci. 2016; 17: 497-511
        • Sun H.
        • Damez-Werno D.M.
        • Scobie K.N.
        • Shao N.Y.
        • Dias C.
        • Rabkin J.
        • et al.
        ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior.
        Nat Med. 2015; 21: 1146-1153
        • Hunsberger J.G.
        • Newton S.S.
        • Bennett A.H.
        • Duman C.H.
        • Russell D.S.
        • Salton S.R.
        • et al.
        Antidepressant actions of the exercise-regulated gene VGF.
        Nat Med. 2007; 13: 1476-1482
        • Cattaneo A.
        • Sesta A.
        • Calabrese F.
        • Nielsen G.
        • Riva M.A.
        • Gennarelli M.
        The expression of VGF is reduced in leukocytes of depressed patients and it is restored by effective antidepressant treatment.
        Neuropsychopharmacology. 2010; 35: 1423-1428
        • Jiang H.
        • Chen S.
        • Lu N.
        • Yue Y.
        • Yin Y.
        • Zhang Y.
        • et al.
        Reduced serum VGF levels were reversed by antidepressant treatment in depressed patients.
        World J Biol Psychiatry. 2017; 18: 586-591
        • Ramos A.
        • Rodriguez-Seoane C.
        • Rosa I.
        • Trossbach S.V.
        • Ortega-Alonso A.
        • Tomppo L.
        • et al.
        Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: Its downregulation by DISC1.
        Hum Mol Genet. 2014; 23: 5859-5865
        • Alder J.
        • Thakker-Varia S.
        • Bangasser D.A.
        • Kuroiwa M.
        • Plummer M.R.
        • Shors T.J.
        • et al.
        Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity.
        J Neurosci. 2003; 23: 10800-10808
        • Thakker-Varia S.
        • Alder J.
        Neuropeptides in depression: Role of VGF.
        Behav Brain Res. 2009; 197: 262-278
        • Behnke J.
        • Cheedalla A.
        • Bhatt V.
        • Bhat M.
        • Teng S.
        • Palmieri A.
        • et al.
        Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms.
        Int J Mol Sci. 2017; 18: E612
        • Duman R.S.
        • Aghajanian G.K.
        Synaptic dysfunction in depression: Potential therapeutic targets.
        Science. 2012; 338: 68-72
        • LaPlant Q.
        • Vialou V.
        • Covington 3rd, H.E.
        • Dumitriu D.
        • Feng J.
        • Warren B.L.
        • et al.
        Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.
        Nat Neurosci. 2010; 13: 1137-1143
        • Covington 3rd, H.E.
        • Maze I.
        • Sun H.
        • Bomze H.M.
        • DeMaio K.D.
        • Wu E.Y.
        • et al.
        A role for repressive histone methylation in cocaine-induced vulnerability to stress.
        Neuron. 2011; 71: 656-670
        • Pena C.J.
        • Bagot R.C.
        • Labonte B.
        • Nestler E.J.
        Epigenetic signaling in psychiatric disorders.
        J Mol Biol. 2014; 426: 3389-3412
        • Covington 3rd, H.E.
        • Vialou V.F.
        • LaPlant Q.
        • Ohnishi Y.N.
        • Nestler E.J.
        Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition.
        Neurosci Lett. 2011; 493: 122-126
        • Covington 3rd, H.E.
        • Maze I.
        • LaPlant Q.C.
        • Vialou V.F.
        • Ohnishi Y.N.
        • Berton O.
        • et al.
        Antidepressant actions of histone deacetylase inhibitors.
        J Neurosci. 2009; 29: 11451-11460
        • Misztak P.
        • Panczyszyn-Trzewik P.
        • Sowa-Kucma M.
        Histone deacetylases (HDACs) as therapeutic target for depressive disorders.
        Pharmacol Rep. 2018; 70: 398-408
        • Christoffel D.J.
        • Golden S.A.
        • Russo S.J.
        Structural and synaptic plasticity in stress-related disorders.
        Rev Neurosci. 2011; 22: 535-549
        • Holtmaat A.
        • Svoboda K.
        Experience-dependent structural synaptic plasticity in the mammalian brain.
        Nat Rev Neurosci. 2009; 10: 647-658
        • Yoshihara Y.
        • De Roo M.
        • Muller D.
        Dendritic spine formation and stabilization.
        Curr Opin Neurobiol. 2009; 19: 146-153
        • Restivo L.
        • Vetere G.
        • Bontempi B.
        • Ammassari-Teule M.
        The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex.
        J Neurosci. 2009; 29: 8206-8214
        • Vetere G.
        • Restivo L.
        • Cole C.J.
        • Ross P.J.
        • Ammassari-Teule M.
        • Josselyn S.A.
        • et al.
        Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory.
        Proc Natl Acad Sci U S A. 2011; 108: 8456-8460
        • Basu S.
        • Lamprecht R.
        The role of actin cytoskeleton in dendritic spines in the maintenance of long-term memory.
        Front Mol Neurosci. 2018; 11: 143
        • Salton S.R.
        • Ferri G.L.
        • Hahm S.
        • Snyder S.E.
        • Wilson A.J.
        • Possenti R.
        • et al.
        VGF: A novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance.
        Front Neuroendocrinol. 2000; 21: 199-219
        • Jiang C.
        • Lin W.J.
        • Sadahiro M.
        • Labonte B.
        • Menard C.
        • Pfau M.L.
        • et al.
        VGF function in depression and antidepressant efficacy.
        Mol Psychiatry. 2018; 23: 1632-1642
        • Sha L.
        • MacIntyre L.
        • Machell J.A.
        • Kelly M.P.
        • Porteous D.J.
        • Brandon N.J.
        • et al.
        Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3.
        Mol Psychiatry. 2012; 17: 267-279
        • Moon S.M.
        • Kim J.S.
        • Park B.R.
        • Kim D.K.
        • Kim S.G.
        • Kim H.J.
        • et al.
        Transcriptional regulation of the neuropeptide VGF by the neuron-restrictive silencer factor/neuron-restrictive silencer element.
        Neuroreport. 2015; 26: 144-151
        • Lin P.
        • Wang C.
        • Xu B.
        • Gao S.
        • Guo J.
        • Zhao X.
        • et al.
        The VGF-derived peptide TLQP62 produces antidepressant-like effects in mice via the BDNF/TrkB/CREB signaling pathway.
        Pharmacol Biochem Behav. 2014; 120: 140-148

      Linked Article

      • Histone Crotonylation Makes Its Mark in Depression Research
        Biological PsychiatryVol. 85Issue 8
        • Preview
          Emerging evidence of critical roles for chromatin dysregulation in neuropsychiatric pathologies has added to our understanding as to how transcriptional programs in the brain may be disrupted to precipitate maladaptive behaviors. Posttranslational modifications (PTMs) on histone tails are one well-studied mechanism through which chromatin can be modulated by environmental insults over the course of a lifetime. Such perturbations (e.g., chronic stress) can increase an individual’s risk for neuropsychiatric syndromes, including major depressive disorder, posttraumatic stress disorder, and other affective illnesses.
        • Full-Text
        • PDF