Grant: Project Grant

Transcription is the first step in gene expression. Transcription is largely regulated by transcription factors (TFs) and chromatin regulators. There are hundreds of thousands of enhancers, DNA regions bound by TFs, throughout the mammalian genome. Enhancers play key roles in cell type-specific gene activation during embryonic development. However, our understanding of how multiple TFs selectively recognize and activate functional enhancers out of thousands of similar TF-binding sites on the gnome and how chromatin regulators contribute to the specificity and function of cell-type-specific enhancers remains remarkably incomplete. Motor neuron specification is one of the key developmental processes in the central nervous system. Isl1 and Onecut1 are key programming TFs for motor neuron specification. We found that Isl1 and Onecut1 TFs co-bind to enhancer DNA in maturing motor neurons. The gene regulatory mechanisms through which enhancers are bound by Isl1 and Onecut1 and activated for gene expression in neural development remain elusive. To examine the regulatory mechanisms of the enhancers contributing to motor neuron gene expression, we will test whether Isl1 functions as an integrator TF of neuronal enhancers in motor neurons. We will examine the genomic mechanisms of long-range chromatin interactions between motor neuron enhancers and target gene promoters. We will also investigate how chromatin regulatory proteins change chromatin structure to activate enhancer DNA during embryonic development. Our studies will potentially provide critical impacts on the transition from studying cell fate specification to the more efficient production of functional cell types for disease modeling. In combination, our study will provide important insight into the molecular processes that translate TF-binding patterns into cell-type-specific gene expression at the genomic level.