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

Mol Psychiatry. 2022 Aug;27(8):3343-3354. doi: 10.1038/s41380-022-01566-y.

Chia-Wen Lin ¹ ², Dian E Septyaningtrias ^# ¹, Hsu-Wen Chao ^# ³ ⁴, Mikiko Konda ⁵, Koji Atarashi ⁵ ⁶, Kozue Takeshita ⁵, Kota Tamada ¹ ⁷, Jun Nomura ¹ ⁷, Yohei Sasagawa ⁸ ⁹, Kaori Tanaka ⁸ ⁹ ¹⁰, Itoshi Nikaido ⁸ ⁹ ¹⁰, Kenya Honda ⁵ ⁶, Thomas J McHugh ², Toru Takumi ¹¹ ¹² ¹³

Affiliations

1 Laboratory for Mental Biology, RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan.
2 Laboratory for Circuit and Behavioral Physiology, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
3 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
4 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
5 Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.
6 RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, 230-0045, Japan.
7 Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, 650-0017, Japan.
8 Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, 351-0198, Japan.
9 Functional Genome Informatics, Division of Medical Genomics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, 113-8510, Japan.
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.
11 Laboratory for Mental Biology, RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan. takumit@med.kobe-u.ac.jp.
12 Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, 650-0017, Japan. takumit@med.kobe-u.ac.jp.
13 RIKEN Center for Biosystems Dynamics Research, Chuo, Kobe, 650-0047, Japan. takumit@med.kobe-u.ac.jp.
# Contributed equally.

PMID: 35491410 DOI: 10.1038/s41380-022-01566-y

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.