Overview

Early life experience not only shapes our brains and behaviors, but impacts our risk for developing disease throughout our life. But how do our genes and environment combine to shape our developing brains? 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. The cause of neurodevelopmental disorders is complex and involves both genetic and environmental risk factors. A multitude of early-life environmental exposures and maternal health conditions increase the risk of neurodevelopmental disorders, including maternal immune activation and pollutant exposure during pregnancy. Disruption of epigenetic processes regulating brain developmental has been proposed as a potential mechanism linking environmental and genetic risk. The Ciernia laboratory combines experimental and computational approaches to understand how epigenetic mechanisms regulate gene expression across our lifespan. The lab specifically focuses on mechanisms of epigenetic regulation in multiple brain cell populations across normal brain and immune system development and in rodent models of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). We test novel hypotheses linking genetic and environmental risk factors to altered patterns of gene expression, epigenomic regulatory pathways, cellular function and animal behavior. Findings from our research will increase our understanding of the basic mechanisms regulating gene expression in the brain and form the basis for future development of novel immune targeted therapeutics for neurodevelopmental disorders such as ASD.

Publications

Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats
Translational Psychiatry
Elizabeth L. Berg and Lauren R. Pedersen and Michael C. Pride and Stela P. Petkova and Kelley T. Patten and Anthony E. Valenzuela and Christopher Wallis and Keith J. Bein and Anthony Wexler and Pamela J. Lein and Jill L. Silverman
DOI: 10.1038/s41398-020-00978-0
12/2020

19.3 DEVELOPMENTAL EXPOSURE TO NEAR-ROADWAY POLLUTION PRODUCES BEHAVIORAL AND HISTOLOGICAL PHENOTYPES RELEVANT TO NEURODEVELOPMENTAL DISORDERS
Journal of the American Academy of Child & Adolescent Psychiatry
Jill L. Silverman and Elizabeth L. Berg and Kelley T. Patten and Anthony E. Valenzuela and Christopher Wallis and Janine M. LaSalle and Annie Vogel Ciernia and Keith J. Bein and Anthony S. Wexler and Pamela J. Lein
DOI: 10.1016/j.jaac.2020.07.660
10/2020

Epigenomic Convergence of Neural-Immune Risk Factors in Neurodevelopmental Disorder Cortex
Cerebral Cortex
A Vogel Ciernia and B I Laufer and H Hwang and K W Dunaway and C E Mordaunt and R L Coulson and D H Yasui and J M LaSalle
DOI: 10.1093/cercor/bhz115
03/2020

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy
Epilepsia
Hannah K. Kim and Tilo Gschwind and Theresa M. Nguyen and Anh D. Bui and Sylwia Felong and Kristen Ampig and David Suh and Annie V. Ciernia and Marcelo A. Wood and Ivan Soltesz
DOI: 10.1111/epi.16445
03/2020

Genetic variants drive altered epigenetic regulation of endotoxin tolerance in BTBR macrophages
Annie Vogel Ciernia and Verena M. Link and Milo Careaga and Janine LaSalle and Paul Ashwood
DOI: 10.1101/2020.02.08.940296
02/2020

Abstract # 3247 Genetic variants drive altered epigenetic regulation of endotoxin tolerance in BTBR macrophages
Brain, Behavior, and Immunity
A. Vogel Ciernia and M. Careaga and J. LaSalle and P. Ashwood
DOI: 10.1016/j.bbi.2019.08.042
10/2019

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights
Epigenetics
Benjamin I. Laufer and Hyeyeon Hwang and Annie Vogel Ciernia and Charles E. Mordaunt and Janine M. LaSalle
DOI: 10.1080/15592294.2019.1609867
07/2019

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome.
Human molecular genetics
DOI: 10.1093/hmg/ddy301
PubMed: 30137367
12/2018

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights
Benjamin I. Laufer and Hyeyeon Hwang and Annie Vogel Ciernia and Charles E. Mordaunt and Janine M. LaSalle
DOI: 10.1101/428482
09/2018

Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory.
Nature communications
DOI: 10.1038/s41467-018-05868-0
PubMed: 30127461
08/2018

Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism
Glia
Annie Vogel Ciernia and Milo Careaga and Janine M. LaSalle and Paul Ashwood
DOI: 10.1002/glia.23261
03/2018

Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches
Epigenetics
Annie Vogel Ciernia and Benjamin I . Laufer and Keith W. Dunaway and Charles E. Mordaunt and Rochelle L. Coulson and Theresa S. Totah and Danielle S. Stolzenberg and Jaime C. Frahm and Akanksha Singh-Taylor and Tallie Z. Baram and Janine M. LaSalle and Dag H. Yasui
DOI: 10.1080/15592294.2018.1451720
03/2018

UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons.
Epigenetics
DOI: 10.1080/15592294.2017.1376151
PubMed: 28925810
11/2017

Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex
Rochelle L. Coulson and Dag H. Yasui and Keith Dunaway and Benjamin I. Laufer and Annie Vogel Ciernia and Charles E. Mordaunt and Theresa S. Totah and Janine M. LaSalle
DOI: 10.1101/184788
09/2017

Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering.
Human molecular genetics
DOI: 10.1093/hmg/ddx087
PubMed: 28334953
05/2017

Mutation of neuron-specific chromatin remodeling subunit BAF53b: rescue of plasticity and memory by manipulating actin remodeling.
Learning & memory (Cold Spring Harbor, N.Y.)
DOI: 10.1101/lm.044602.116
PubMed: 28416631
04/2017

Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes.
Cell reports
DOI: 10.1016/j.celrep.2016.11.058
PubMed: 27974215
12/2016

The landscape of DNA methylation amid a perfect storm of autism aetiologies.
Nature reviews. Neuroscience
DOI: 10.1038/nrn.2016.41
PubMed: 27150399
05/2016

Visual Attention to Dynamic Scenes of Ambiguous Provocation and Children's Aggressive Behavior.
Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53
DOI: 10.1080/15374416.2016.1138412
PubMed: 27027935
03/2016

Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation.
The Journal of Neuroscience
DOI: 10.1523/JNEUROSCI.3682-15.2016
PubMed: 27013687
03/2016

Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition.
Neuron
DOI: 10.1016/j.neuron.2014.10.032
PubMed: 25467983
11/2014

Examining object location and object recognition memory in mice.
Current protocols in neuroscience
DOI: 10.1002/0471142301.ns0831s69
PubMed: 25297693
10/2014

Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.
Neuropharmacology
DOI: 10.1016/j.neuropharm.2013.10.002
PubMed: 24140580
10/2013

Targeting H3K4 trimethylation in Huntington disease.
Proceedings of the National Academy of Sciences of the United States of America
DOI: 10.1073/pnas.1311323110
PubMed: 23872847
07/2013

The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory.
Nature neuroscience
DOI: 10.1038/nn.3359
PubMed: 23525042
03/2013

Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory.
Learning & memory (Cold Spring Harbor, N.Y.)
DOI: 10.1101/lm.026385.112
PubMed: 23161447
11/2012

Molecular brake pad hypothesis: pulling off the brakes for emotional memory.
Reviews in the neurosciences
DOI: 10.1515/revneuro-2012-0050
PubMed: 23096102
01/2012

Research

Signatures of Microglial Dysfunction across Autism Spectrum Disorders (ASD) Models
Gene expression patterns and cellular morphology changes in human post-mortem ASD brain indicate increased microglial activation. However, it is unclear how changes in microglial function contribute to ASD, and if the observed immune signatures are a cause or consequence of altered brain development. To parse the role of microglia in ASD we are examining both genetic and environmental mouse models to address: When do microglial abnormalities arise during brain development? and How do altered microglial-neuronal interactions impact cellular development?
We hypothesize that the microglial transcriptome is altered in ASD mouse models across development and at least a subset of microglial genes are commonly disrupted across models. To test this hypothesis, we are examining changes in microglial gene expression and morphology from genetic and environmental ASD risk mouse models at multiple developmental timepoints. The long-term goal of this work is to identify common pathways of dysfunction that are conserved across different mouse models and in human ASD that can serve as novel biomarkers or therapeutic targets.

Epigenomic Regulation of Microglial Development
The goal of this project is to characterize and causally test the interplay of multiple epigenomic regulatory mechanisms in coordinating microglial maturation during normal brain development. During maturation microglia must coordinate specific patterns of gene expression for migration, differentiation, and establishment of a homeostatic state in the brain. This precise regulation of gene expression requires interactions with the maturing nervous system and is orchestrated by epigenetic mechanisms that allow both dynamic control of gene expression and stable, long-term cellular differentiation. We are utilizing a variety of epigenomic sequencing techniques combined with advanced bioinformatic and statistical modelling to understand microglial gene regulation across development.

Chromatin Remodeling in Neurodevelopmental Disorders
Mutations in 12 of the 29 subunit genes that compose the BAF (Brg1 Associated Factor) chromatin remodelling complex have been identified in ASD and Intellectual Disability, making it one of the most common genetically implicated protein complexes in neurodevelopmental disorders. However, it is unclear how mutations in this epigenetic regulator lead to childhood disorders. My lab is examining Baf53b, a subunit that confers neuronal specificity to the neuronal version of the BAF complex (nBAF). Baf53b is expressed exclusively in neurons and is only found within the nBAF complex, making it an ideal target for genetic manipulations to elucidate nBAF’s role in brain development. My lab will test the hypothesis that conditional deletion of Baf53b within specific neuronal populations during brain development in mice disrupts chromatin regulation. We will link the gene regulatory functions of nBAF to the development of relevant behaviours and deficits in neuronal connectivity and synapse maturation, allowing us to pinpoint the cell types, time points and gene targets regulated by nBAF. Our findings will provide mechanistic insight into a unique, neuronal epigenetic mechanism that is critical for normal brain development and highly relevant to therapeutic development for numerous childhood disorders including ASD, ID and epilepsy.

Grants

2019-2024: Canadian Institutes of Health Research. Tier 2 Canada Research Chair in Understanding Gene Expression in the Brain. Role: PI Salary Award

2019-2022: SickKids Foundation in partnership with the Canadian Institutes of Health Research. New Investigator Research Grant: The Role of Baf53b in Regulating Neuronal Gene Expression, Synaptic Function and Autism Behaviours Across Development. Role: PI

2019-2024: Canadian Foundation for Innovation. John R. Evans Leaders Fund. Role: PI

2019-2024: UBC Start-up Funding with the Department of Biochemistry and Molecular Biology and the Djavad Mowafaghian Centre for Brain Health. Role: PI

2019-2024: Natural Sciences and Engineering Council of Canada. Discovery Grant: Epigenomic Regulation In Microglia. Role: PI

2020-2021: DMCBH Kickstart Award. Pilot award for examining endotoxin tolerance using in vivo imaging. Role: PI

2019-2020: Natural Sciences and Engineering Council of Canada. Discovery Launch Supplement. Role: PI

2018-2019: Brain and Behavior Research Foundation. NARSAD Young Investigator Award: The Role of MeCP2 Isoform 1 in Rett Syndrome Disease Progression. Role: PI

2018-2019: National Institutes of Mental Health. Research Scientist Development Award: Mapping Multi-Omics Networks in Microglia Across Autism Models. Role: PI

Honours & Awards

2018: University of California Davis Postdoctoral Excellence in Research Award

2018: Postdoctoral Research Conference Oral Presentation Second Place Award

2019: Cold Spring Harbor Laboratory Leadership in Biosciences course fellowship

2017: Allen Brain Institute Summer Workshop on the Dynamic Brain Faculty Choice Award

2017: Allen Brain Institute Summer Workshop on the Dynamic Brain Fellowship

2017: UC Davis Postdoctoral Scholars Association Travel Award

2017: UC Davis Psychology Conference Oral Presentation Winner

2017: Postdoctoral Research Conference Oral Presentation Winner

2016: Helmsley Scholarship to attend Cold Spring Harbor Laboratory Statistical Methods for Functional Genomics workshop

2014: Autism Research Training Fellowship Program, University of California, Davis MIND Institute

2013: UCI Center for Cognitive Neuroscience and Engineering Graduate Merit Fellowship

2013: James L. McGaugh Award for Excellence in Graduate Research in Neurobiology and Behavior

2013: American College of Neuropsychopharmacology (ACNP) Travel Award

2013: Renee Harwick Advanced CNLM Graduate Student Award

2013: Top Graduate Oral Presentation at the 24th Science Conference of the Graduate Women in Science

2013: ReMIND Outstanding Presentation at the Emerging Scientist Symposium

2012: Second Prize Data Blitz at the CNLM Conference on the Neurobiology of Learning and Memory

2012: Achievement Rewards for College Scientists (ARCS) Fellowship ($20,000 award)

2012: Graduate Student Chapter Travel Award, Society for Neuroscience

2012-2013: Aging Training Grant (T32-AG00096-29)

2012: Roger Russell’s Scholar Award in The Neurobiology of Learning and Memory

2011: Graduate Fellow Award, HHMI-UCI Teaching Fellows Program

2011: Edward Steinhaus Teaching Award

2009-2010: Cellular and Molecular Neuroscience Training Grant (T32-NS007444)