A scalable platform for the development of cell-type-specific viral drivers

Elife. 2019 Sep 23;8:e48089. doi: 10.7554/eLife.48089.

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.

Keywords: AAV; PESCA; cell-type-specific; enhancers; genetics; genomics; mouse; neuroscience; somatostatin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cerebral Cortex / physiology
  • Gene Expression Regulation / drug effects*
  • Genes, Regulator
  • Genetic Vectors
  • Interneurons / physiology
  • Mice
  • Molecular Biology / methods*
  • Neurons / drug effects*
  • Neurophysiology / methods*
  • Recombinant Proteins / biosynthesis*
  • Recombinant Proteins / genetics
  • Somatostatin / metabolism*
  • Viruses / genetics*

Substances

  • Recombinant Proteins
  • Somatostatin

Associated data

  • GEO/GSE136802