An expansion of the non-coding genome and its regulatory potential underlies vertebrate neuronal diversity.

Proper assembly and function of the nervous system requires the generation of a uniquely diverse population of neurons expressing a cell-type-specific combination of effector genes that collectively define neuronal morphology, connectivity, and function. How countless partially overlapping but cell-type-specific patterns of gene expression are controlled at the genomic level remains poorly understood. Here we show that neuronal genes are associated with highly complex gene regulatory systems composed of independent cell-type- and cell-stage-specific regulatory elements that reside in expanded non-coding genomic domains. Mapping enhancer-promoter interactions revealed that motor neuron enhancers are broadly distributed across the large chromatin domains. This distributed regulatory architecture is not a unique property of motor neurons but is employed throughout the nervous system. The number of regulatory elements increased dramatically during the transition from invertebrates to vertebrates, suggesting that acquisition of new enhancers might be a fundamental process underlying the evolutionary increase in cellular complexity. • Neuronal genes have expanded intergenic domain size and regulatory complexity • Neuronal genes are controlled by distinct cell- and stage-specific enhancers • Neuronal enhancers are not clustered but distributed across expanded non-coding DNA • Neuronal gene regulation expanded during transition from invertebrates to vertebrates Closser et al. show that neuronal genes are associated with highly complex regulatory systems in expanded non-coding genomic domains. Neuronal enhancers are distributed broadly and utilized sparsely in cell-type- and cell-stage-specific patterns. Acquisition of new enhancers might be a fundamental process underlying the evolutionary increase in cellular complexity. [ABSTRACT FROM AUTHOR]