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Neurobiological functions of transcriptional enhancers

Nature Neuroscience volume 23, pages 5–14 (2020)Cite this article

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Abstract

Transcriptional enhancers are regulatory DNA elements that underlie the specificity and dynamic patterns of gene expression. Over the past decade, large-scale functional genomics projects have driven transformative progress in our understanding of enhancers. These data have relevance for identifying mechanisms of gene regulation in the CNS, elucidating the function of non-coding regulatory sequences in neurobiology and linking sequence variation within enhancers to genetic risk for neurological and psychiatric disorders. However, the sheer volume and complexity of genomic data presents a challenge to interpreting enhancer function in normal and pathogenic neurobiological processes. Here, to advance the application of genome-scale enhancer data, we offer a primer on current models of enhancer function in the CNS, we review how enhancers regulate gene expression across the neuronal lifespan, and we suggest how emerging findings regarding the role of non-coding sequence variation offer opportunities for understanding brain disorders and developing new technologies for neuroscience.

The human brain is arguably the most complex machine on Earth. The functions of the brain are the subject of our greatest fascinations, while the dysfunction of brain disorders represents a large and growing economic and societal burden. The genome encodes the rules for the construction and function of the brain, and it also harbors causes of disease susceptibility. The challenge for our post-genomic era is to decode how dynamic and cell-type-specific genome function emerges from static sequence. Although the territory of the genome is vast, direct transcriptional control is concentrated in regulatory elements that comprise only a fraction of the total genome1, narrowing the search space. Enhancers are the most common regulatory elements in mammalian genomes, with hundreds of thousands of enhancers predicted to coordinate transcriptional regulation in the brain2. Comparative analysis of these enhancer elements across CNS cell types and disease states holds clues to the basis of brain evolution, the wonders of cognition and the devastation of neurological disorders.

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Fig. 1: Enhancer function is dependent on sequence and context.
Fig. 2: General models of CNS regulatory wiring.
Fig. 3: Enhancers across the neuronal lifespan.
Fig. 4: How disease-associated SNPs impact enhancer function.

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Acknowledgements

This work was supported by NIH R35GM119831 (A.S.N.) and R01NS098804 (A.E.W.).

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Authors and Affiliations

  1. Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, CA, USA

    Alex S. Nord

  2. Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA

    Alex S. Nord

  3. Department of Neurobiology, Duke University School of Medicine, Durham, NC, USA

    Anne E. West

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  1. Alex S. Nord
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A.S.N. and A.E.W. conceived of the review, researched the literature, wrote the manuscript and revised the manuscript.

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Correspondence to Alex S. Nord or Anne E. West.

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Peer review information Nature Neuroscience thanks Erica Korb, Ian Maze, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Nord, A.S., West, A.E. Neurobiological functions of transcriptional enhancers. Nat Neurosci 23, 5–14 (2020). https://doi.org/10.1038/s41593-019-0538-5

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