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

被引：10

作者：

Lin, Chia-Wen ^{[1
,2
]}

Septyaningtrias, Dian E. ^{[1
]}

Chao, Hsu-Wen ^{[3
,4
]}

Konda, Mikiko ^{[5
]}

Atarashi, Koji ^{[5
,6
]}

Takeshita, Kozue ^{[5
]}

Tamada, Kota ^{[1
,7
]}

Nomura, Jun ^{[1
,7
]}

Sasagawa, Yohei ^{[8
,9
]}

Tanaka, Kaori ^{[8
,9
,10
]}

Nikaido, Itoshi ^{[8
,9
,10
]}

Honda, Kenya ^{[5
,6
]}

McHugh, Thomas J. ^{[2
]}

Takumi, Toru ^{[1
,7
,11
]}

机构：

[1] RIKEN Brain Sci Inst, Lab Mental Biol, Wako, Saitama 3510198, Japan

[2] RIKEN Ctr Brain Sci, Lab Circuit & Behav Physiol, Wako, Saitama 3510198, Japan

[3] Taipei Med Univ, Sch Med, Dept Physiol, Coll Med, Taipei 110, Taiwan

[4] Taipei Med Univ, Grad Inst Med Sci, Coll Med, Taipei 110, Taiwan

[5] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 1608582, Japan

[6] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan

[7] Kobe Univ, Sch Med, Dept Physiol & Cell Biol, Chuo Ku, Kobe, Hyogo 6500017, Japan

[8] RIKEN Ctr Biosyst Dynam Res, Lab Bioinformat Res, Wako, Saitama 3510198, Japan

[9] Tokyo Med & Dent Univ, Med Res Inst, Div Med Genom, Funct Genome Informat,Bunkyo Ku, Tokyo 1138510, Japan

[10] Univ Tsukuba, Grad Sch Sci & Technol, Degree Programs Syst & Informat Engn, Masters Doctoral Program Life Sci Innovat Bioinfo, Tsukuba, Ibaraki 3058577, Japan

[11] RIKEN Ctr Biosyst Dynam Res, Chuo Ku, Kobe, Hyogo 6500047, Japan

来源：

MOLECULAR PSYCHIATRY | 2022年 / 27卷 / 08期

基金：

日本学术振兴会;

关键词：

ACTIVATION; BRAIN; REGULATORS; GENETICS; DEFICITS; NETWORK; CORTEX; CELLS; ACID;

D O I：

10.1038/s41380-022-01566-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3343 / 3354

页数：12

共 1 条

[1] A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model
Chia-Wen Lin
Dian E. Septyaningtrias
Hsu-Wen Chao
Mikiko Konda
Koji Atarashi
Kozue Takeshita
Kota Tamada
Jun Nomura
Yohei Sasagawa
Kaori Tanaka
Itoshi Nikaido
Kenya Honda
Thomas J. McHugh
Toru Takumi
Molecular Psychiatry, 2022, 27 : 3343 - 3354

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