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A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model

Molecular Psychiatry volume 27, pages 3343–3354 (2022)Cite this article

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Abstract

Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.

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Fig. 1: Single-cell RNA-seq analysis of AGM progenitor cells identified alteration of HDAC1-mediated transcriptional repression in delaying the process of endothelial-to-hematopoietic transition (EHT).
Fig. 2: Single-cell RNA-seq analysis of YS progenitors also identified HDAC1 as the pathogenic factor.
Fig. 3: A shared mechanism underlying the pathologic progenitors can be modulated at specific developmental windows to restore immune dysregulation.
Fig. 4: Pathologic progenitor causes immune dysregulation and dysbiosis in the gut microbiome.

Data availability

All the sequencing data that support the findings of this study have been deposited in the Gene Expression Omnibus with the accession code GSE197618.

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Acknowledgements

We thank all technical staff of Takumi laboratory for their assistance, with special thanks to K. Yanaka for the assistance with FACS analysis, Y. Nomura, and Y. Kusakari for the assistance with 10x genomics library preparation. We also thank S. Chikuma (Keio University) for his instruction and discussion on BMT experiments and M. Izumi (RIKEN Nishina Center for Accelerator-Based Science) for the guidance on usage and maintenance of X-ray generator. We are grateful to the Support Unit for Animal Resources Development and the Support Unit for Bio-Material Analysis, RIKEN CBS Research Resources Division, with special thanks to T. Arai for mouse embryo manipulation and K. Ohtawa for the technical support with FACS analysis and single-cell sorting for quartez-seq2. We thank D. Polygalov (Laboratory for Circuit and Behavioral Physiology, RIKEN CBS) for his assistance on SCENIC analysis. For Quartz-seq2, we thank A. Matsushima and M. Ishii (RIKEN BDR) for assistance with the infrastructure for the data analysis; H. Danno (Knowledge Palette, Inc.) for the development of data analysis software for single-cell transcriptomes.

Funding

C-WL was supported by fellowships from the Japan Society for the Promotion of Science (JSPS) and the Tokyo Biochemical Research Foundation (TBRF). This work was in part supported by KAKENHI (15F15105, 16H06316, 16H06463, 19K16529, 21H00202, 21H04813, 21K19351) from JSPS and the Ministry of Education, Culture, Sports, Science, and Technology, Japan Agency for Medical Research and Development (AMED) under Grant Number JP21wm0425011, Intramural Research Grant (30-9) for Neurological and Psychiatric Disorders of NCNP, the Takeda Science Foundation, Smoking Research Foundation, SENSHIN Medical Research Foundation, TBRF, Hyogo Science and Technology Association, Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics, Taiju Life Social Welfare Foundation, Naito Foundation, JST CREST (JPMJCR16G3), RIKEN Epigenetics Program, RIKEN Epigenome Control Program, and the Projects for Technological Development, and Research Center Network for Realization of Regenerative Medicine from AMED.

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Author notes

  1. These authors contributed equally: Dian E. Septyaningtrias, Hsu-Wen Chao.

Authors and Affiliations

  1. Laboratory for Mental Biology, RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan

    Chia-Wen Lin, Dian E. Septyaningtrias, Kota Tamada, Jun Nomura & Toru Takumi

  2. Laboratory for Circuit and Behavioral Physiology, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan

    Chia-Wen Lin & Thomas J. McHugh

  3. Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan

    Hsu-Wen Chao

  4. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan

    Hsu-Wen Chao

  5. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan

    Mikiko Konda, Koji Atarashi, Kozue Takeshita & Kenya Honda

  6. RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, 230-0045, Japan

    Koji Atarashi & Kenya Honda

  7. Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, 650-0017, Japan

    Kota Tamada, Jun Nomura & Toru Takumi

  8. Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, 351-0198, Japan

    Yohei Sasagawa, Kaori Tanaka & Itoshi Nikaido

  9. Functional Genome Informatics, Division of Medical Genomics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, 113-8510, Japan

    Yohei Sasagawa, Kaori Tanaka & Itoshi Nikaido

  10. Master’s/Doctoral Program in Life Science Innovation (Bioinformatics), Degree Programs in Systems and Information Engineering, Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan

    Kaori Tanaka & Itoshi Nikaido

  11. RIKEN Center for Biosystems Dynamics Research, Chuo, Kobe, 650-0047, Japan

    Toru Takumi

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Contributions

C-WL and TT conceived the study. C-WL performed or was involved in all experiments. MK, KA, KTakeshita, and KH performed 16S rRNA metagenomic sequencing. DES performed 10x genomics single-cell RNA-seq and the FACS analysis. JN helped singe-cell RNA-seq analysis. YS, KTanaka, and IN performed Quarz-seq2. C-WL wrote the paper, with editing provided by KA, KTamada, H-WC, TJM, and TT.

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Correspondence to Toru Takumi.

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Lin, CW., Septyaningtrias, D.E., Chao, HW. et al. A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model. Mol Psychiatry 27, 3343–3354 (2022). https://doi.org/10.1038/s41380-022-01566-y

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