Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior.
Animals
Dorsal Raphe Nucleus
/ metabolism
Histones
/ metabolism
Male
Female
Stress, Psychological
/ metabolism
Humans
Antidepressive Agents
/ pharmacology
Depressive Disorder, Major
/ metabolism
Mice
Serotonin
/ metabolism
Mice, Inbred C57BL
Epigenesis, Genetic
/ drug effects
Behavior, Animal
/ drug effects
Gene Expression Regulation
/ drug effects
Social Defeat
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 Jun 2024
13 Jun 2024
Historique:
received:
18
09
2023
accepted:
28
05
2024
medline:
14
6
2024
pubmed:
14
6
2024
entrez:
13
6
2024
Statut:
epublish
Résumé
Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.
Identifiants
pubmed: 38871707
doi: 10.1038/s41467-024-49336-4
pii: 10.1038/s41467-024-49336-4
doi:
Substances chimiques
Histones
0
Antidepressive Agents
0
Serotonin
333DO1RDJY
histone H3 trimethyl Lys4
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5042Subventions
Organisme : NIMH NIH HHS
ID : R01 MH116900
Pays : United States
Organisme : NIMH NIH HHS
ID : F31 MH116588
Pays : United States
Organisme : NIMH NIH HHS
ID : F32 MH126534
Pays : United States
Organisme : NIMH NIH HHS
ID : K99 MH120334
Pays : United States
Organisme : NINDS NIH HHS
ID : F99 NS125774
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Warnick, S. J. Jr., Mehdi, L. & Kowalkowski, J. Wait-there’s evidence for that? Integrative medicine treatments for major depressive disorder. Int. J. Psychiatry Med. 56, 334–343 (2021).
pubmed: 34521233
doi: 10.1177/00912174211046353
Duman, R. S., Aghajanian, G. K., Sanacora, G. & Krystal, J. H. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238–249 (2016).
pubmed: 26937618
pmcid: 5405628
doi: 10.1038/nm.4050
Mendlewicz, J. Towards achieving remission in the treatment of depression. Dialogues Clin. Neurosci. 10, 371–375 (2008).
pubmed: 19170394
pmcid: 3181889
doi: 10.31887/DCNS.2008.10.4/jmendlewicz
Blier, P. & El Mansari, M. Serotonin and beyond: therapeutics for major depression. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20120536 (2013).
pubmed: 23440470
pmcid: 3638389
doi: 10.1098/rstb.2012.0536
Moncrieff, J. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol. Psychiatry 28, 3243–3256 (2023).
pubmed: 35854107
doi: 10.1038/s41380-022-01661-0
Berger, M., Gray, J. A. & Roth, B. L. The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009).
pubmed: 19630576
pmcid: 5864293
doi: 10.1146/annurev.med.60.042307.110802
Huang, K. W. et al. Molecular and anatomical organization of the dorsal raphe nucleus. Elife 8, e46464 (2019).
pubmed: 31411560
pmcid: 6726424
doi: 10.7554/eLife.46464
Kohler, S., Cierpinsky, K., Kronenberg, G. & Adli, M. The serotonergic system in the neurobiology of depression: relevance for novel antidepressants. J. Psychopharmacol. 30, 13–22 (2016).
pubmed: 26464458
doi: 10.1177/0269881115609072
Wainwright, S. R. & Galea, L. A. The neural plasticity theory of depression: assessing the roles of adult neurogenesis and PSA-NCAM within the hippocampus. Neural Plast. 2013, 805497 (2013).
pubmed: 23691371
pmcid: 3649690
doi: 10.1155/2013/805497
Morrissette, D. A. & Stahl, S. M. Modulating the serotonin system in the treatment of major depressive disorder. CNS Spectr. 19, 57–67 (2014).
pubmed: 25544378
doi: 10.1017/S1092852914000613
Fouquet, G., Coman, T., Hermine, O. & Cote, F. Serotonin, hematopoiesis and stem cells. Pharm. Res 140, 67–74 (2019).
doi: 10.1016/j.phrs.2018.08.005
Wirth, A., Holst, K. & Ponimaskin, E. How serotonin receptors regulate morphogenic signalling in neurons. Prog. Neurobiol. 151, 35–56 (2017).
pubmed: 27013076
doi: 10.1016/j.pneurobio.2016.03.007
Kolodziejczak, M. et al. Serotonin modulates developmental microglia via 5-HT2B receptors: potential implication during synaptic refinement of retinogeniculate projections. ACS Chem. Neurosci. 6, 1219–1230 (2015).
pubmed: 25857335
doi: 10.1021/cn5003489
Hirschfeld, R. M. History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61, 4–6 (2000).
pubmed: 10775017
Colgan, L. A., Putzier, I. & Levitan, E. S. Activity-dependent vesicular monoamine transporter-mediated depletion of the nucleus supports somatic release by serotonin neurons. J. Neurosci. 29, 15878–15887 (2009).
pubmed: 20016104
pmcid: 2796554
doi: 10.1523/JNEUROSCI.4210-09.2009
Young, A. B., Pert, C. D., Brown, D. G., Taylor, K. M. & Snyder, S. H. Nuclear localization of histamine in neonatal rat brain. Science 173, 247–249 (1971).
pubmed: 5104178
doi: 10.1126/science.173.3993.247
Walther, D. J. et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell 115, 851–862 (2003).
pubmed: 14697203
doi: 10.1016/S0092-8674(03)01014-6
Farrelly, L. A. et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567, 535–539 (2019).
pubmed: 30867594
pmcid: 6557285
doi: 10.1038/s41586-019-1024-7
Lepack, A. E. et al. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science 368, 197–201 (2020).
pubmed: 32273471
pmcid: 7228137
doi: 10.1126/science.aaw8806
Zheng, Q. et al. Histone monoaminylation dynamics are regulated by a single enzyme and promote neural rhythmicity. bioRxiv https://www.biorxiv.org/content/10.1101/2022.12.06.519310v1 (2022).
Sardar, D. et al. Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation. Science 380, eade0027 (2023).
pubmed: 37319217
pmcid: 10874521
doi: 10.1126/science.ade0027
Lukasak, B. J. et al. TGM2-mediated histone transglutamination is dictated by steric accessibility. Proc. Natl Acad. Sci. USA 119, e2208672119 (2022).
pubmed: 36256821
pmcid: 9618071
doi: 10.1073/pnas.2208672119
Al-Kachak, A. & Maze, I. Post-translational modifications of histone proteins by monoamine neurotransmitters. Curr. Opin. Chem. Biol. 74, 102302 (2023).
pubmed: 37054563
pmcid: 10225327
doi: 10.1016/j.cbpa.2023.102302
Zhao, S. et al. Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout. Proc. Natl. Acad. Sci. USA 118, e2016742118 (2021).
pubmed: 33526675
pmcid: 8017887
doi: 10.1073/pnas.2016742118
Fulton, S. L. et al. Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats. Neuropsychopharmacology 47, 1776–1783 (2022).
pubmed: 35094023
pmcid: 9372029
doi: 10.1038/s41386-022-01279-4
Stewart, A. F., Lepack, A. E., Fulton, S. L., Safovich, P. & Maze, I. Histone H3 dopaminylation in nucleus accumbens, but not medial prefrontal cortex, contributes to cocaine-seeking following prolonged abstinence. Mol. Cell Neurosci. 125, 103824 (2023).
pubmed: 36842545
pmcid: 10247417
doi: 10.1016/j.mcn.2023.103824
Sun, H., Kennedy, P. J. & Nestler, E. J. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38, 124–137 (2013).
pubmed: 22692567
doi: 10.1038/npp.2012.73
Nagy, C., Vaillancourt, K. & Turecki, G. A role for activity-dependent epigenetics in the development and treatment of major depressive disorder. Genes Brain Behav. 17, e12446 (2018).
pubmed: 29251832
doi: 10.1111/gbb.12446
Kronman, H. et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat. Neurosci. 24, 667–676 (2021).
pubmed: 33723435
pmcid: 8216773
doi: 10.1038/s41593-021-00814-8
Maitra, S. et al. Histone lysine demethylase JMJD2D/KDM4D and family members mediate effects of chronic social defeat stress on mouse hippocampal neurogenesis and mood disorders. Brain Sci. 10, 833 (2020).
pubmed: 33182385
pmcid: 7695311
doi: 10.3390/brainsci10110833
Hamilton, P. J. et al. Cell-type-specific epigenetic editing at the fosb gene controls susceptibility to social defeat stress. Neuropsychopharmacology 43, 272–284 (2018).
pubmed: 28462942
doi: 10.1038/npp.2017.88
Khandelwal, N., Dey, S. K., Chakravarty, S. & Kumar, A. miR-30 family miRNAs mediate the effect of chronic social defeat stress on hippocampal neurogenesis in mouse depression model. Front. Mol. Neurosci. 12, 188 (2019).
pubmed: 31440139
pmcid: 6694739
doi: 10.3389/fnmol.2019.00188
Liu, B., Liu, J., Wang, M., Zhang, Y. & Li, L. From serotonin to neuroplasticity: evolvement of theories for major depressive disorder. Front. Cell Neurosci. 11, 305 (2017).
pubmed: 29033793
pmcid: 5624993
doi: 10.3389/fncel.2017.00305
Miyanishi, H., Muramatsu, S. I. & Nitta, A. Striatal Shati/Nat8l-BDNF pathways determine the sensitivity to social defeat stress in mice through epigenetic regulation. Neuropsychopharmacology 46, 1594–1605 (2021).
pubmed: 34099867
pmcid: 8280178
doi: 10.1038/s41386-021-01033-2
Qian, W. et al. Depressive-like behaviors induced by chronic social defeat stress are associated with HDAC7 reduction in the nucleus accumbens. Front. Psychiatry 11, 586904 (2020).
pubmed: 33574772
doi: 10.3389/fpsyt.2020.586904
Golden, S. A., Covington, H. E. 3rd, Berton, O. & Russo, S. J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6, 1183–1191 (2011).
pubmed: 21799487
pmcid: 3220278
doi: 10.1038/nprot.2011.361
Liu, Y. et al. Chromodomain Y-like protein-mediated histone crotonylation regulates stress-induced depressive behaviors. Biol. Psychiatry 85, 635–649 (2019).
pubmed: 30665597
doi: 10.1016/j.biopsych.2018.11.025
Sun, H. et al. BAZ1B in nucleus accumbens regulates reward-related behaviors in response to distinct emotional stimuli. J. Neurosci. 36, 3954–3961 (2016).
pubmed: 27053203
pmcid: 4821908
doi: 10.1523/JNEUROSCI.3254-15.2016
Fang, W. et al. Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J. Affect. Disord. 260, 302–313 (2020).
pubmed: 31521867
doi: 10.1016/j.jad.2019.09.013
Covington, H. E. et al. Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition. Neurosci. Lett. 493, 122–126 (2011).
pubmed: 21335060
pmcid: 3074929
doi: 10.1016/j.neulet.2011.02.022
Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).
pubmed: 17956738
doi: 10.1016/j.cell.2007.09.018
Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).
pubmed: 16469931
doi: 10.1126/science.1120972
Kornstein, S. G. et al. Gender differences in chronic major and double depression. J. Affect. Disord. 60, 1–11 (2000).
pubmed: 10940442
doi: 10.1016/S0165-0327(99)00158-5
Picco, L., Subramaniam, M., Abdin, E., Vaingankar, J. A. & Chong, S. A. Gender differences in major depressive disorder: findings from the Singapore Mental Health Study. Singap. Med. J. 58, 649–655 (2017).
doi: 10.11622/smedj.2016144
Sramek, J. J., Murphy, M. F. & Cutler, N. R. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin. Neurosci. 18, 447–457 (2016).
pubmed: 28179816
pmcid: 5286730
doi: 10.31887/DCNS.2016.18.4/ncutler
Takahashi, A. et al. Establishment of a repeated social defeat stress model in female mice. Sci. Rep. 7, 12838 (2017).
pubmed: 28993631
pmcid: 5634448
doi: 10.1038/s41598-017-12811-8
Newman, E. L. et al. Fighting females: neural and behavioral consequences of social defeat stress in female mice. Biol. Psychiatry 86, 657–668 (2019).
pubmed: 31255250
pmcid: 6788975
doi: 10.1016/j.biopsych.2019.05.005
Newman, E. L., Covington, H. E. 3rd, Leonard, M. Z., Burk, K. & Miczek, K. A. Hypoactive thalamic Crh+ cells in a female mouse model of alcohol drinking after social trauma. Biol. Psychiatry 90, 563–574 (2021).
pubmed: 34281710
pmcid: 8463500
doi: 10.1016/j.biopsych.2021.05.022
Connor, D. A. & Gould, T. J. Chronic fluoxetine ameliorates adolescent chronic nicotine exposure-induced long-term adult deficits in trace conditioning. Neuropharmacology 125, 272–283 (2017).
pubmed: 28778833
pmcid: 5757519
doi: 10.1016/j.neuropharm.2017.07.033
Maze, I. et al. Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87, 77–94 (2015).
pubmed: 26139371
pmcid: 4491146
doi: 10.1016/j.neuron.2015.06.014
Matthews, G. A. et al. Dorsal raphe dopamine neurons represent the experience of social isolation. Cell 164, 617–631 (2016).
pubmed: 26871628
pmcid: 4752823
doi: 10.1016/j.cell.2015.12.040
Monteggia, L. M. et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol. Psychiatry 61, 187–197 (2007).
pubmed: 16697351
doi: 10.1016/j.biopsych.2006.03.021
Risso, D., Ngai, J., Speed, T. P. & Dudoit, S. Normalization of RNA-seq data using factor analysis of control genes or samples. Nat. Biotechnol. 32, 896–902 (2014).
pubmed: 25150836
pmcid: 4404308
doi: 10.1038/nbt.2931
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Cahill, K. M., Huo, Z., Tseng, G. C., Logan, R. W. & Seney, M. L. Improved identification of concordant and discordant gene expression signatures using an updated rank-rank hypergeometric overlap approach. Sci. Rep. 8, 9588 (2018).
pubmed: 29942049
pmcid: 6018631
doi: 10.1038/s41598-018-27903-2
Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).
pubmed: 23586463
pmcid: 3637064
doi: 10.1186/1471-2105-14-128
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
pubmed: 27141961
pmcid: 4987924
doi: 10.1093/nar/gkw377
Xie, Z. et al. Gene set knowledge discovery with Enrichr. Curr. Protoc. 1, e90 (2021).
pubmed: 33780170
pmcid: 8152575
doi: 10.1002/cpz1.90
Lepack, A. E. et al. Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior. Proc. Natl Acad. Sci. USA 113, 12562–12567 (2016).
pubmed: 27791098
pmcid: 5098673
doi: 10.1073/pnas.1608270113
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
pubmed: 18798982
pmcid: 2592715
doi: 10.1186/gb-2008-9-9-r137
Shen, L. et al. diffReps: detecting differential chromatin modification sites from ChIP-seq data with biological replicates. PLoS One 8, e65598 (2013).
pubmed: 23762400
pmcid: 3677880
doi: 10.1371/journal.pone.0065598
Bilimoria, P. M. & Bonni, A. Cultures of cerebellar granule neurons. CSH Protoc. 2008, pdb prot5107 (2008).
pubmed: 21356753
Kong, L. et al. A primary role of TET proteins in establishment and maintenance of de novo bivalency at CpG islands. Nucleic Acids Res. 44, 8682–8692 (2016).
pubmed: 27288448
pmcid: 5062965
doi: 10.1093/nar/gkw529