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

Lin, Chia-Wen; Septyaningtrias, Dian Eurike; Chao, Hsu; Konda, Mikiko; Atarashi, Koji; Takeshita, Kozue; Tamada, Kota; Nomura, Jun; Sasagawa, Yohei; Tanaka, Kaori; Nikaido, Itoshi; Honda, Kenya; McHugh, Thomas J.; Takumi, Toru

doi:10.1038/s41380-022-01566-y

Cited by 10 publications

(7 citation statements)

References 67 publications

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“…In contrast, BTBR/J mice had a more significant reduction of Lachnospiraceae/Ruminococcaceaem bacteria (Supplementary Table S4), whose lives are tightly associated with the regulatory T cells. This feature is consistent with the observations in the peripheral immune system and echoes our previous conclusion about the causality between immune dysregulation and gut dysbiosis [9].…”

Section: Resultssupporting

confidence: 93%

“…Another intriguing observation was that BTBR/R and BTBR/J have different copies of the CNV-carrying HDAC1 gene (Table 1, chr4: 129204618-129205791), suggesting different expression levels of HDAC1 in the two BTBR strains. In our previous study, we found that a disturbed epigenetic mechanism mediated by HDAC1 affects the development of microglia and hematopoietic stem cell (HSC), which leads respectively to immune dysregulation in the brain and the peripheral immune system of BTBR/R mice [9]. Since microglia and HSC have different epigenetic demands for their development, the varying levels of HDAC1 in BTBR/R and BTBR/J may account for the divergent immune phenotype in the two BTBR strains.…”

Section: Accelerated De Novo Rate Of Cnv Formation In Btbr Strainsmentioning

confidence: 99%

“…In addition to germ cells, a previous study also demonstrated increased expression of Class II ERV in BTBR/J embryos [49], which prompted us to verify the impact of active ERV during developmental stages. By re-accessing our previous single-cell transcriptome data sets of E11.5 embryonic aortagonad-mesonephros (AGM) and E10.5 yolk sac (YS) in BTBR/R [9] (Supplementary Fig. S5a, b), we analyzed multiple cell types including progenitor cells across definitive hematopoiesis to evaluate the effect of ubiquitous ERV existence (Supplementary Fig.…”

Section: Embryonic Erv Activation Evades Integrated Stress Response A...mentioning

confidence: 99%

“…It is interesting to note that inbred strains genetically close to BTBR/J, such as 129 × 1/SvJ strain [6,8], show similar autism-like behavioral features, suggesting the existence of autism genetic susceptibility among mouse inbred strains. By using a sister strain of BTBR TF/ArtRbrc (hereafter referred to as BTBR/R), we recently discovered a disturbed epigenetic mechanism leads to the pathologic origins of systemic immune dysregulation in this strain by affecting definitive hematopoiesis in the yolk sac and aortagonad-mesonephros [9]. Together, these results suggest the BTBR strain as a potential model to investigate the multiple-hit theory of autism [2,4].…”

Section: Introductionmentioning

confidence: 99%

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An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

et al. 2023

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The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

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Section: Resultssupporting

confidence: 93%

Section: Accelerated De Novo Rate Of Cnv Formation In Btbr Strainsmentioning

confidence: 99%

Section: Embryonic Erv Activation Evades Integrated Stress Response A...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

et al. 2023

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“…Also, the knockdown of EHMT1 in NSCs promotes a differentiated state [ 439 ]. A novel inbred strain BTBR/R idiopathic ASD model gains copy number variants (CNVs) in HDAC1, contributing to epigenetic reprogramming and immune dysfunction during embryogenesis at E11.5 [ 440 , 441 ]. In addition, impairments in HDAC are involved in SHANK3 mutations in Phelan-McDermid syndrome [ 442 ].…”

Section: Convergence Of Prenatal Vpa Exposure Compared To Other Model...mentioning

confidence: 99%

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder

Zarate-Lopez,

Torres-Chávez,

Gálvez-Contreras

et al. 2024

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models.

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The early life exposome and autism risk: a role for the maternal microbiome?

Di Gesù,

Buffington

2024

Gut Microbes

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Autism spectrum disorders (ASD) are highly heritable, heterogeneous neurodevelopmental disorders characterized by clinical presentation of atypical social, communicative, and repetitive behaviors. Over the past 25 years, hundreds of ASD risk genes have been identified. Many converge on key molecular pathways, from translational control to those regulating synaptic structure and function. Despite these advances, therapeutic approaches remain elusive. Emerging data unearthing the relationship between genetics, microbes, and immunity in ASD suggest an integrative physiology approach could be paramount to delivering therapeutic breakthroughs. Indeed, the advent of large-scale multi-OMIC data acquisition, analysis, and interpretation is yielding an increasingly mechanistic understanding of ASD and underlying risk factors, revealing how genetic susceptibility interacts with microbial genetics, metabolism, epigenetic (re)programming, and immunity to influence neurodevelopment and behavioral outcomes. It is now possible to foresee exciting advancements in the treatment of some forms of ASD that could markedly improve quality of life and productivity for autistic individuals. Here, we highlight recent work revealing how gene X maternal exposome interactions influence risk for ASD, with emphasis on the intrauterine environment and fetal neurodevelopment, host–microbe interactions, and the evolving therapeutic landscape for ASD.

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

Cited by 10 publications

References 67 publications

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder

The early life exposome and autism risk: a role for the maternal microbiome?

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