During brain development, cells that will form the various structures and layers of the mature brain go through waves of proliferation, migration, differentiation, and maturation to form the different cell types of the brain. Control of gene expression enables cells to make the different proteins required at different stages and across different functions, from developmental transcription factors to lineage-specific neurotransmitters. Similarly, control of gene expression enables cells to maintain homeostasis and respond to environmental stimuli. Our group investigates the complex regulatory circuitry that enables tight transcriptional control, including the primary DNA sequences, the higher order epigenetic structure of chromatin, the transcription factors and other DNA and chromatin-associated proteins, and finally the transcribed RNA and translated protein products.
Cis-regulatory elements and regulatory circuits in brain development
Cis-regulatory elements are DNA sequences that act as control switches to activate or repress transcription of target genes. These elements drive expression patterns that are specific to cell type, region, and developmental stage in the brain. We focus on regulatory elements called enhancers, which activate target genes via transcription factor binding, promoter looping, and transcriptional activation. The big question driving our work is can we combine information from experiments that examine transcription factor binding, epigenetic state, and gene expression to understand the regulatory circuits well enough to model cellular lineage specification and neuronal function in the brain? Such an understanding is critical to unlocking the biology of brain development and evolution as well as understanding neurodevelopmental disorders such as autism, epilepsy, and schizophrenia.
Lab projects in this area:
- Understanding the genomic basis of lineage specification in the brain (collaboration with John Rubenstein (UCSF))
- Using mouse models to identify mechanisms and pathology linking mutations to chromatin remodeling genes such as Chd8 and neurodevelopmental disorders (funded by UC Davis MIND Institute Pilot Award and NIGMS)
- Functional approaches to understanding the sequence-encoded function of enhancers (funded by NIGMS and SFARI)
Gene regulation in rodent models of neurological disorders
Mouse and rat models have been critical to understanding neurological disorders, enabling the study of brain development and function in mammalian models. Our group examines genetic and environmental models of neurological disorders, investigating how changes in gene expression linked to pathology are regulated. Current areas of focus include autism spectrum disorders, epilepsy, schizophrenia, and traumatic brain injury. Our goal is to understand the epigenetic-mediated contribution of gene expression to these disorders, and, ultimately, to developing treatments by re-balancing expression by genetic and epigenetic modulation.
- Using genomics to map acute and chronic pathology in a rat model of traumatic brain injury (collaboration with Gene Gurkoff and Bruce Lyeth (UCD))
- Mouse models to study the phenotypes produced by enhancer mutations linked to autism spectrum disorders and epilepsy (funded by SFARI and the Dravet Syndrome Foundation)
- Linking maternal immune activation to neurodevelopmental pathology via genomic analysis (collaboration with Kim McAllister (UCD), funded by NARSAD)
Clinical applications of genomics
The findings from human genetic studies drive much of our research, and a constant goal is to strengthen the connections between clinical research, to basic science and animal models, and back to translational approaches to improve clinical care.
Funding (Nord PI)
- National Institute of General Medical Sciences R35
- Simons Foundation Autism Research Initiative Pilot Award
- Dravet Syndrome Foundation Research Grant
- Brains and Behavior Foundation (NARSAD Young Investigator Award)
- UC Davis MIND Institute Pilot Award