Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription

Abstract

Large-scale genetic screening has identified KMT5B (SUV420H1), which encodes a histone H4 K20 di- and tri-methyltransferase highly expressed in prefrontal cortex (PFC), as a top-ranking high-risk gene for autism. However, the biological function of KMT5B in the brain is poorly characterized, and how KMT5B deficiency is linked to autism remains largely unknown. Here we knocked down Kmt5b in PFC and examined behavioral and electrophysiological changes, as well as underlying molecular mechanisms. Mice with Kmt5b deficiency in PFC display social deficits, a core symptom of autism, without the alteration of other behaviors. Kmt5b deficiency also produces deficits in PFC glutamatergic synaptic transmission, which is accompanied by the reduced synaptic expression of glutamate receptor subunits and associated proteins. Kmt5b deficiency-induced reduction of H4K20me2 impairs 53BP1-mediated DNA repair, leading to the elevation of p53 expression and its target gene Ddit4 (Redd1), which is implicated in synaptic impairment. RNA-sequencing data indicate that Kmt5b deficiency results in the upregulation of genes enriched in cellular stress response and ubiquitin-dependent protein degradation. Collectively, this study has revealed the functional role of Kmt5b in the PFC, and suggests that Kmt5b deficiency could cause autistic phenotypes by inducing synaptic dysfunction and transcriptional aberration.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: KMT5B knockdown in PFC.
Fig. 2: Behavioral changes in mice with Kmt5b deficiency in PFC.
Fig. 3: Decreased synaptic transmission in Kmt5b-deficient PFC.
Fig. 4: Increased DNA damage, p53, and Ddit4 expression in Kmt5b-deficient PFC.
Fig. 5: Transcriptomic changes in Kmt5b-deficient PFC.

Data availability

Genomic data will be deposited in a public repository.

References

  1. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51:431–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Stessman HA, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017;49:515–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74:285–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. RK CY, Merico D, Bookman M, J LH, Thiruvahindrapuram B, Patel RV, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci. 2017;20:602–11.

    Article  CAS  Google Scholar 

  7. Satterstrom FK, Kosmicki J, Wang J, Breen MS, De Rubeis S, An JY, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell. 2020;180:568–84.e23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E, et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 2008;22:2048–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Lyu G, Guan Y, Zhang C, Zong L, Sun L, Huang X, et al. TGF-beta signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging. Nat Commun. 2018;9:2560.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. Jorgensen S, Schotta G, Sorensen CS. Histone H4 lysine 20 methylation: key player in epigenetic regulation of genomic integrity. Nucleic Acids Res. 2013;41:2797–806.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Paquin KL, Howlett NG. Understanding the histone DNA repair code: H4K20me2 makes its mark. Mol Cancer Res. 2018;16:1335–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Suberbielle E, Sanchez PE, Kravitz AV, Wang X, Ho K, Eilertson K, et al. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-beta. Nat Neurosci. 2013;16:613–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 2004;18:1251–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Evertts AG, Manning AL, Wang X, Dyson NJ, Garcia BA, Coller HA. H4K20 methylation regulates quiescence and chromatin compaction. Mol Biol Cell. 2013;24:3025–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448:553–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Pusalkar M, Suri D, Kelkar A, Bhattacharya A, Galande S, Vaidya VA. Early stress evokes dysregulation of histone modifiers in the medial prefrontal cortex across the life span. Dev Psychobiol. 2016;58:198–210.

    CAS  PubMed  Article  Google Scholar 

  18. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.

    CAS  PubMed  Article  Google Scholar 

  19. Goldman-Rakic PS. Cellular basis of working memory. Neuron. 1995;14:477–85.

    CAS  PubMed  Article  Google Scholar 

  20. Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006;7:268–77.

    CAS  PubMed  Article  Google Scholar 

  21. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306:2001–10.

    CAS  PubMed  Article  Google Scholar 

  22. Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, et al. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014;370:1209–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Qin L, Ma K, Wang ZJ, Hu Z, Matas E, Wei J, et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci. 2018;21:564–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Krueger DD, Osterweil EK, Chen SP, Tye LD, Bear MF. Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome. Proc Natl Acad Sci USA. 2011;108:2587–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, et al. Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry. 2020;25:2517–33.

    CAS  PubMed  Article  Google Scholar 

  26. Rapanelli M, Tan T, Wang W, Wang X, Wang ZJ, Zhong P, et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry 2019; Epub ahead of print.

  27. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;106–107:1–16.

    PubMed  Article  Google Scholar 

  28. Baloch S, Verma R, Huang H, Khurd P, Clark S, Yarowsky P, et al. Quantification of brain maturation and growth patterns in C57BL/6J mice via computational neuroanatomy of diffusion tensor images. Cereb Cortex. 2009;19:675–87.

    PubMed  Article  Google Scholar 

  29. Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999;2:861–3.

    CAS  PubMed  Article  Google Scholar 

  30. Sturman DA, Moghaddam B. The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendencies. Neurosci Biobehav Rev. 2011;35:1704–12.

    PubMed  PubMed Central  Article  Google Scholar 

  31. Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Rein B, Ma K, Yan Z. A standardized social preference protocol for measuring social deficits in mouse models of autism. Nat Protoc. 2020;15:3464–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC. Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci. 2016;17:45–59.

    CAS  PubMed  Article  Google Scholar 

  35. Wang W, Rein B, Zhang F, Tan T, Zhong P, Qin L, et al. Chemogenetic activation of prefrontal cortex rescues synaptic and behavioral deficits in a mouse model of 16p11.2 deletion syndrome. J Neurosci. 2018;38:5939–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Tan T, Wang W, Williams J, Ma K, Cao Q, Yan Z. Stress exposure in dopamine D4 receptor knockout mice induces schizophrenia-like behaviors via disruption of GABAergic transmission. Schizophr Bull. 2019;45:1012–23.

    PubMed  Article  Google Scholar 

  37. Rein B, Tan T, Yang F, Wang W, Williams J, Zhang F, et al. Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry 2020; Epub ahead of print.

  38. Yang H, Pesavento JJ, Starnes TW, Cryderman DE, Wallrath LL, Kelleher NL, et al. Preferential dimethylation of histone H4 lysine 20 by Suv4-20. J Biol Chem. 2008;283:12085–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Hsiao KY, Mizzen CA. Histone H4 deacetylation facilitates 53BP1 DNA damage signaling and double-strand break repair. J Mol Cell Biol. 2013;5:157–65.

    CAS  PubMed  Article  Google Scholar 

  40. Sharma A, Singh K, Almasan A. Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol. 2012;920:613–26.

    CAS  PubMed  Article  Google Scholar 

  41. Nelson WG, Kastan MB. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol. 1994;14:1815–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8:275–83.

    CAS  PubMed  Article  Google Scholar 

  43. Cuella-Martin R, Oliveira C, Lockstone HE, Snellenberg S, Grolmusova N, Chapman JR. 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms. Mol Cell. 2016;64:51–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis—the p53 network. J Cell Sci. 2003;116:4077–85.

    CAS  PubMed  Article  Google Scholar 

  45. Tedeschi A, Di Giovanni S. The non-apoptotic role of p53 in neuronal biology: enlightening the dark side of the moon. EMBO Rep. 2009;10:576–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, et al. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell. 2002;10:995–1005.

    CAS  PubMed  Article  Google Scholar 

  47. Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat Med. 2014;20:531–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol (1985). 2002;92:2177–86.

    CAS  Article  Google Scholar 

  49. Richey JA, Rittenberg A, Hughes L, Damiano CR, Sabatino A, Miller S, et al. Common and distinct neural features of social and non-social reward processing in autism and social anxiety disorder. Soc Cogn Affect Neurosci. 2014;9:367–77.

    PubMed  Article  Google Scholar 

  50. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell. 2006;127:1361–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Wong S, Napoli E, Krakowiak P, Tassone F, Hertz-Picciotto I, Giulivi C Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study. Pediatrics 2016;137.

  52. Araghi-Niknam M, Fatemi SH. Levels of Bcl-2 and P53 are altered in superior frontal and cerebellar cortices of autistic subjects. Cell Mol Neurobiol. 2003;23:945–52.

    CAS  PubMed  Article  Google Scholar 

  53. Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX, et al. BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res. 2010;88:2641–7.

    CAS  PubMed  Google Scholar 

  54. Sahin M, Sur M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science. 2015;350:aab38971–8.

    Article  CAS  Google Scholar 

  55. Bagni C, Zukin RS. A synaptic perspective of fragile X syndrome and autism spectrum disorders. Neuron. 2019;101:1070–88.

    CAS  PubMed  Article  Google Scholar 

  56. Wellmann S, Truss M, Bruder E, Tornillo L, Zelmer A, Seeger K, et al. The RNA-binding protein RBM3 is required for cell proliferation and protects against serum deprivation-induced cell death. Pediatr Res. 2010;67:35–41.

    CAS  PubMed  Article  Google Scholar 

  57. Stopka T, Skoultchi AI. The ISWI ATPase Snf2h is required for early mouse development. Proc Natl Acad Sci USA. 2003;100:14097–102.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Goodwin LR, Picketts DJ. The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. Mol Cell Neurosci. 2018;87:55–64.

    CAS  PubMed  Article  Google Scholar 

  59. Wu T, Merbl Y, Huo Y, Gallop JL, Tzur A, Kirschner MW. UBE2S drives elongation of K11-linked ubiquitin chains by the anaphase-promoting complex. Proc Natl Acad Sci USA. 2010;107:1355–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Z-JW performed animal surgery, immunocytochemical, biochemical, behavioral experiments and analyzed data. She also participated in bioinformatics analyses, and wrote parts of the draft. BR participated in bioinformatics analyses, some biochemical experiments, and wrote parts of the draft. PZ performed electrophysiological experiments and analyzed data. JW and FY performed bioinformatic analysis of genomic data. QC performed some biochemical experiments. FZ participated in some behavioral experiments. KM and QC generated Kmt5b shRNA AAV plasmid. ZY designed experiments, supervised the project, and wrote the paper.

Corresponding author

Correspondence to Zhen Yan.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, ZJ., Rein, B., Zhong, P. et al. Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription. Neuropsychopharmacol. 46, 1617–1626 (2021). https://doi.org/10.1038/s41386-021-01029-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-021-01029-y

Further reading

Search

Quick links