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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022
Y1 - 2022
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.
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U2 - 10.1038/s41380-022-01566-y
DO - 10.1038/s41380-022-01566-y
M3 - Article
AN - SCOPUS:85129152901
SN - 1359-4184
JO - Molecular Psychiatry
JF - Molecular Psychiatry
ER -
