TY - JOUR
T1 - A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model
AU - Lin, Chia Wen
AU - Septyaningtrias, Dian E.
AU - Chao, Hsu Wen
AU - Konda, Mikiko
AU - Atarashi, Koji
AU - Takeshita, Kozue
AU - Tamada, Kota
AU - Nomura, Jun
AU - Sasagawa, Yohei
AU - Tanaka, Kaori
AU - Nikaido, Itoshi
AU - Honda, Kenya
AU - McHugh, Thomas J.
AU - Takumi, Toru
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85129152901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129152901&partnerID=8YFLogxK
U2 - 10.1038/s41380-022-01566-y
DO - 10.1038/s41380-022-01566-y
M3 - Article
AN - SCOPUS:85129152901
SN - 1359-4184
VL - 27
SP - 3343
EP - 3354
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -
