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Publications of the Week

Genetic Variants Drive Altered Epigenetic Regulation of Endotoxin Response in BTBR Macrophages

By June 4, 2020No Comments

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This week we profile a recent publication in Brain, Behavior, and Immunity from the laboratory of Dr.
Annie Vogel Ciernia (pictured, fourth from right) at the Djavad Mowafaghian Centre for Brain Health.

Can you provide a brief overview of your lab’s current research focus?

The work described in the new paper was done at the end of my postdoc at UC Davis in the USA as part of a collaborative project between Dr. Janine LaSalle and Dr. Paul Ashwood’s laboratories. Both Dr. LaSalle and Ashwood are members of the UC Davis MIND Institute where I did my postdoctoral training in the Autism Research Training Program. Dr. Ashwood’s lab focuses on altered immune function in children with Autism Spectrum Disorder (ASD) and Dr. LaSalle’s lab focuses on epigenetic regulation in ASD. By combining the expertise of both labs, I focused this project on understanding how immune genes are regulated in a mouse model of ASD.

My own independent laboratory at UBC is in the Department of Biochemistry and Molecular Biology and located within the Djavad Mowafaghian Centre for Brain Health. My lab is driven by the “big question” of how our genes and environment combine to shape our developing brains. Early life experience not only shapes our brains and behaviours but impacts our risk for developing disease throughout our life. Epigenetic mechanisms that control the expression of genes without altering the underlying genetic code allow for cellular adaptation to a changing environment. These fundamental mechanisms control cellular differentiation, producing the vast diversity of cells in the body. They are also likely disrupted in many neurodevelopmental and neuropsychiatric disorders.

My lab combines experimental and computational approaches to understand how epigenetic mechanisms regulate gene expression across our lifespan. We specifically focus on mechanisms of epigenetic regulation in multiple brain cell populations across normal brain and immune system development and in rodent models of neurodevelopmental disorders. We test novel hypotheses linking genetic and environmental risk factors to altered patterns of gene expression, epigenomic regulation, cellular function and animal behaviour. We aim to expand our understanding of the basic mechanisms regulating gene expression in the brain and apply these findings in the search for novel therapeutic targets for neurodevelopmental disorders.

What is the significance of the findings in this publication?

This work examines how genetics and environment influence immune system regulation in a mouse model of ASD. We used the BTBR model, a naturally occurring genetic strain of mice that show lower levels of social behaviours and increased repetitive behaviours compared to the standard lC57 la mouse. These behavioural changes are similar to impairments observed in children with ASD and have been linked to genetic differences between the two strains, making the BTBR a commonly used model for ASD. Another interesting characteristic of the BTBR mice is that they have high levels of inflammatory markers including enhanced expression of cytokines in blood and brain. Similar immune differences have been previously observed by Dr. Ashwood’s lab in a subset of children with ASD compared to typically developing controls. We sought to try to understand the mechanisms controlling immune gene expression in immune cells from the BTBR compared to C57, using cultured bone marrow derived macrophages (BMDM) from juvenile male mice of both strains. We specifically looked at the ability of the BMDM cultures to induce immune tolerance, the ability to suppress inflammatory gene expression following repeated immune activations. This form of tolerance is critical for preventing immune cells from over-reacting to commonly present or benign pathogens in the environment. After repeated treatment with lipopolysaccharide to mimic bacterial infections, we identified changes in chromatin accessibility using ATAC-seq at multiple promoters and regulatory regions between the two strains. The epigenetic changes were enriched for genetic variants between the two strains, suggesting that at least a subset of the chromatin changes were influenced by genetic changes. In the C57 a subset of immune genes showed the predicted pattern of tolerized gene expression (decreased with repeated exposures). More than half of these C57 tolerized genes failed to tolerize in the BTBR cells and instead often increased in expression. The failure to tolerize was significantly related to changes in chromatin at the gene promoters, supporting a link between chromatin regulation and altered immune gene expression in BTBR.  Together our findings help explain how genetic differences between the two mouse strains lead to changes in immune cell function and gene expression and highlights a potential epigenetic mechanism by which genetic variation may lead to altered immune function in children with ASD.

What are the next steps for this research?

My laboratory is currently working on understanding how epigenetic mechanisms regulate immune cell tolerance in the brain. We are profiling the epigenomes of microglia, the brain’s resident immune cells, in response to repeated immune activating events. We are also working to identify how induction of tolerance influences microglial function in the brain during normal brain development and in models of neurodevelopmental disorders.

This work was funded by:

My postdoctoral work was funded by the National Institutes of Mental Health (USA) and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award). My current laboratory at UBC is supported by CIHR (Tier 2 Canada Research Chair), NSERC, CFI and the SickKids Foundation.

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