Abstract

Enhancers are the primary DNA regulatory elements that confer cell type specificity of gene expression. Recent studies characterizing individual enhancers have revealed their potential to direct heterologous gene expression in a highly cell-type-specific manner. However, it has not yet been possible to systematically identify and test the function of enhancers for each of the many cell types in an organism. We have developed PESCA, a scalable and generalizable method that leverages ATAC- and single-cell RNA-sequencing protocols, to characterize cell-type-specific enhancers that should enable genetic access and perturbation of gene function across mammalian cell types. Focusing on the highly heterogeneous mammalian cerebral cortex, we apply PESCA to find enhancers and generate viral reagents capable of accessing and manipulating a subset of somatostatin-expressing cortical interneurons with high specificity. This study demonstrates the utility of this platform for developing new cell-type-specific viral reagents, with significant implications for both basic and translational research.

Data availability

Sequencing data had been deposited in GEO under accession code GSE136802

The following data sets were generated

Article and author information

Author details

  1. Sinisa Hrvatin

    Department of Neurobiology, Harvard Medical School, Boston, United States
    For correspondence
    shrvatin@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  2. Christopher P Tzeng

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. M Aurel Nagy

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4608-1152
  4. Hume Stroud

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Charalampia Koutsioumpa

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Oren F Wilcox

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Elena G Assad

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jonathan Green

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Christopher D Harvey

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Eric C Griffith

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Michael E Greenberg

    Department of Neurobiology, Harvard Medical School, Boston, United States
    For correspondence
    Michael_Greenberg@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1380-2160

Funding

National Institutes of Health (RF1MH11408101)

  • Michael E Greenberg

National Institutes of Health (5T32AG000222-23)

  • Sinisa Hrvatin

National Institutes of Health (T32GM007753)

  • M Aurel Nagy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IS00000074-3) of Harvard Medical School. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Version history

  1. Received: April 30, 2019
  2. Accepted: September 16, 2019
  3. Accepted Manuscript published: September 23, 2019 (version 1)
  4. Version of Record published: October 3, 2019 (version 2)

Copyright

© 2019, Hrvatin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sinisa Hrvatin
  2. Christopher P Tzeng
  3. M Aurel Nagy
  4. Hume Stroud
  5. Charalampia Koutsioumpa
  6. Oren F Wilcox
  7. Elena G Assad
  8. Jonathan Green
  9. Christopher D Harvey
  10. Eric C Griffith
  11. Michael E Greenberg
(2019)
A scalable platform for the development of cell-type-specific viral drivers
eLife 8:e48089.
https://doi.org/10.7554/eLife.48089

Share this article

https://doi.org/10.7554/eLife.48089

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