Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance

Kun Chen, Xiaoting Luan, Qisha Liu, Jianwei Wang, Xinxia Chang, Antoine M. Snijders, Jian Hua Mao, Julie Secombe, Zhou Dan, Jian Huan Chen, Zibin Wang, Xiao Dong, Chen Qiu, Xiaoai Chang, Dong Zhang, Susan E. Celniker, Xingyin Liu

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients. Here, we use the model organism Drosophila melanogaster to delineate how KDM5 contributes to ID and ASD. We show that reducing KDM5 causes intestinal barrier dysfunction and changes in social behavior that correlates with compositional changes in the gut microbiota. Therapeutic alteration of the dysbiotic microbiota through antibiotic administration or feeding with a probiotic Lactobacillus strain partially rescues the behavioral, lifespan, and cellular phenotypes observed in kdm5-deficient flies. Mechanistically, KDM5 was found to transcriptionally regulate component genes of the immune deficiency (IMD) signaling pathway and subsequent maintenance of host-commensal bacteria homeostasis in a demethylase-dependent manner. Together, our study uses a genetic approach to dissect the role of KDM5 in the gut-microbiome-brain axis and suggests that modifying the gut microbiome may provide therapeutic benefits for ID and ASD patients. Mutations in members of the KDM5 gene family are found in intellectual disability and autism spectrum disorder patients. Chen et al. discovered that KDM5-microbiota interactions contribute to animal social behavior. Drosophila deficient in kdm5 display gut dysbiosis, abnormal social behavior, and aberrant immune activation, which Lactobacillus plantarum administration can improve.

Original languageEnglish (US)
Pages (from-to)537-552.e8
JournalCell Host and Microbe
Volume25
Issue number4
DOIs
StatePublished - Apr 10 2019

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China (NSFC) grants 81671983 and 81871628 , Natural Science Funding BK20161572 from Jiangsu province of China and starting package from NJMU (X. Liu), Young Scientist Funding BK20161025 from Jiangsu province of China (Q.L. and J.W.), Lawrence Berkeley National Laboratory Directed Research and Development (LDRD) program funding under the Microbes to Biomes (M2B) initiative under contract DE AC02-05CH11231 in the USA (J.-H.M., A.M.S., and S.E.C.), National Institutes of Health (NIH, USA) grant R01GM112783 (J.S.), and National Natural Science Foundation of China (NSFC) grant 31671311 (J.-H.C.). The authors thank X. Liu lab members, reviewers’ suggestions, and the Tsinghua Fly Center.

Funding Information:
This work was supported by National Natural Science Foundation of China (NSFC) grants 81671983 and 81871628, Natural Science Funding BK20161572 from Jiangsu province of China and starting package from NJMU (X. Liu), Young Scientist Funding BK20161025 from Jiangsu province of China (Q.L. and J.W.), Lawrence Berkeley National Laboratory Directed Research and Development (LDRD) program funding under the Microbes to Biomes (M2B) initiative under contract DE AC02-05CH11231 in the USA (J.-H.M. A.M.S. and S.E.C.), National Institutes of Health (NIH, USA) grant R01GM112783 (J.S.), and National Natural Science Foundation of China (NSFC) grant 31671311 (J.-H.C.). The authors thank X. Liu lab members, reviewers’ suggestions, and the Tsinghua Fly Center. X. Liu conceived project and designed the study; K.C. X. Luan, X. Liu, Q.L. J.W. Xinxia Chang, C.Q. Z.W. Xiaoai Chang, J.-H.M. J.S. and Z.D. conducted experiments; and J.-H.C. S.E.C. and X.D. performed RNA-seq analysis. All authors performed data analyses and interpretations, and X. Liu organized experimentation and wrote a first draft of the manuscript. K.C. A.M.S. X. Liu, and S.E.C. generated figures. X. Liu, A.M.S. J.-H.M. S.E.C. and J.S. finalized the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • H3K4me3
  • KDM5
  • demethylase
  • gut microbiome
  • social behavior

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