Roles of Chromatin Regulation in Specification of Neuronal Cell Identity

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How a particular cell develops into a final cell type is a long-standing question in developmental biology. My research program examines the mechanisms of chromatin regulation in neuronal gene expression programs, and how chromatin architecture impacts transcription in specification of neuronal cell identity. In the next 5 years, my lab will address the following three research objectives.******1) Determine the chromatin structure affecting the gene expression to specify neuronal cell identity.***2) Comprehensively characterize the mechanisms of neuron-specific chromatin regulation.***3) Examine long-range chromatin interactions of transcription machinery during embryonic development.******To achieve Objective 1, we will examine chromatin organization around the transcription factor-binding sites during motor neuron differentiation. We will use mouse embryonic stem cell culture and transgenic mouse model systems, combined with various genomic methods to determine the genomic requirements of neuron-specific gene expression programs. These approaches will reveal the impact of the neuronal transcription factors on chromatin structure during embryonic development.******In Objective 2, we will conduct two projects that examine how chromatin regulatory proteins control chromatin organization in a cell type-specific manner. First, we will identify neuron-specific chromatin remodelling factors using the CRISPR/Cas9 genome editing system. Second, we will investigate the mechanisms by which chromatin remodelling factors are recruited to target genes by interacting with the neuronal transcription factors.******In Objective 3, we will examine how cis-regulatory elements interact with one another by chromatin looping. In one project, we will develop a new genomic mapping method to detect chromatin interactions between enhancers and core promoters of a particular gene. In a second project, we will test how transcription factors play roles in the long-range control of gene expression during mouse embryonic stem cell differentiation. ******Impact and Training: The results from these objectives will provide a comprehensive understanding of the mechanisms and functions of transcriptional and chromatin regulatory proteins in the process of neuronal gene expression programs. Our results will contribute to the advancement of science by providing new insights, new methodologies, and valuable resources to the broad research community.******Highly qualified personnel (HQP) will play an essential role in conducting the research in my laboratory. Over the 5-year funding period, I will train 15 HQP at all levels (PhD, MSc, BSc). The objectives of my novel research program will provide significant opportunities for HQP to gain highly desired skills in the areas of stem cell, neurobiology, and genomics. The proposed research program will adequately prepare HQP to move on to successful future careers in science.