Epigenetic Abnormalities in Hematopoietic Cells During Fetal Development Cause Idiopathic Autism

An international research group led by Professor Toru Takumi (Senior Visiting Scientist, RIKEN Center for Biosystems Dynamics Research) and researcher Chia-wen Lin from the Graduate School of Medicine at Kobe University has shown that idiopathic autism is caused by epigenetic abnormalities in hematopoietic cells during fetal development, resulting in immune dysregulation in the brain and gut. The study results revealed that in autism, there are immune abnormalities that can be seen in the brain and gut.

It is hoped that further classification of autism pathophysiology will lead to the creation of new treatment strategies for autism and other neurodevelopmental disorders.

The results of this research will be published in Molecular psychiatry Monday, May 2, 2022 (1:00 a.m. BST).

main points

  • In BTBR mice, an animal model of autism, we identified HDAC1 as the etiology of immune abnormalities through single-cell RNA-seq analysis of AGM blood cells.
  • Single-cell RNA-seq analysis of yolk sac hematopoietic cells also identified HDAC1 as the etiology of microglia developmental abnormalities.
  • Regulating HDAC activity at the fetal stage ameliorated brain inflammation and immune dysregulation in BTBR mice.
  • We found that changes in the gut environment, particularly the immune system, lead to abnormalities in the gut microbiota of BTBR mice.

Research fund

Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapid increase in the number of patients. Immune abnormalities, now thought to be the cause of many diseases, also play an important role in the development of autism. Cerebral inflammation and disturbances of the peripheral immune system are frequently observed in autistic patients. Moreover, immune abnormalities are accompanied by abnormalities of the intestinal microbiota, which would also be involved in the pathogenesis of the disease via the brain-gut axis. However, the essential mechanisms underlying these immune abnormalities remain to be elucidated.

Given the critical developmental stages of immune insults and the significant involvement of the immune system in the development of autism, the research team hypothesized that a common etiology underlies widespread immune dysregulation and originates from different types of progenitor cells. The analysis focused on hematopoietic cells from which immune cells are derived, as well as the yolk sac (YS) and aorta-gonad-mesonephros (AGM), which are involved in hematopoiesis at the stage fetal. These findings search for a common ancestor of inflammation in the brain and peripheral immune system abnormalities. In this study, BTBR mice were used as an idiopathic model for autism.

search results

Single-cell RNA sequencing (sc-RNA seq) of BTBR mice traced the origin of immune abnormalities back to the embryonic yolk sac (YS) and aorta-gonad-mesonephros (AGM) stages and identified where macrophages (microglia) and peripheral immune cells differentiate. Definitive hematopoiesis in YS and AGM single-cell level analysis has successfully identified pathological mechanisms at the molecular level in rare progenitor cells at early stages of development. Namely, we found a common mechanism of transcriptional regulation via HDAC1, a histone deacetylase, underlying these pathologies.

We have also shown that manipulating epigenetic mechanisms during specific developmental stages can restore immune abnormalities in brain and peripheral tissues. Namely, we identified histone deacetylase HDAC1 as a common mechanism. Administration of this histone inhibitors (sodium butyrate or romidepsin) at the fetal stage in BTBR mice suppressed elevated inflammatory cytokines and microglial activation.

We further demonstrated that dysregulated immunity can determine gut dysbiosis of specific patterns in autistic mouse models, making potential biomarkers of Treg and gut dysbiosis a means to categorize the immunosupregulated ASD subtype.

From the above, it is clear that the abnormalities of the brain and peripheral organs (such as the intestines) seen in autism are caused by epigenetic abnormalities in the lineage of hematopoietic stem cells, the ancestor of immune cells.

Perspectives

Our findings not only provide the missing piece to solve the long-standing puzzle of systemic immune dysregulation in autism, but also suggest the role of epigenetic disruption as a common etiology among different risk factor models of autism. environmental. Moreover, to develop precision medicine for ASDs in the future, subtyping ASDs based on the mechanism of pathogenesis is a key first step to resolve the heterogeneity of ASDs and open a new avenue for treatment. of ASDs.

Source:

Journal reference:

Lin, C.W., et al (2022) An epigenetic mechanism common to different cellular origins underlies systemic immune dysregulation in an idiopathic autistic mouse model. Molecular psychiatry. doi.org/10.1038/s41380-022-01566-y

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