Cell Reports (Mar 2021)
Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex
- John K. Mich,
- Lucas T. Graybuck,
- Erik E. Hess,
- Joseph T. Mahoney,
- Yoshiko Kojima,
- Yi Ding,
- Saroja Somasundaram,
- Jeremy A. Miller,
- Brian E. Kalmbach,
- Cristina Radaelli,
- Bryan B. Gore,
- Natalie Weed,
- Victoria Omstead,
- Yemeserach Bishaw,
- Nadiya V. Shapovalova,
- Refugio A. Martinez,
- Olivia Fong,
- Shenqin Yao,
- Marty Mortrud,
- Peter Chong,
- Luke Loftus,
- Darren Bertagnolli,
- Jeff Goldy,
- Tamara Casper,
- Nick Dee,
- Ximena Opitz-Araya,
- Ali Cetin,
- Kimberly A. Smith,
- Ryder P. Gwinn,
- Charles Cobbs,
- Andrew L. Ko,
- Jeffrey G. Ojemann,
- C. Dirk Keene,
- Daniel L. Silbergeld,
- Susan M. Sunkin,
- Viviana Gradinaru,
- Gregory D. Horwitz,
- Hongkui Zeng,
- Bosiljka Tasic,
- Ed S. Lein,
- Jonathan T. Ting,
- Boaz P. Levi
Affiliations
- John K. Mich
- Allen Institute for Brain Science, Seattle, WA, USA; Corresponding author
- Lucas T. Graybuck
- Allen Institute for Brain Science, Seattle, WA, USA
- Erik E. Hess
- Allen Institute for Brain Science, Seattle, WA, USA
- Joseph T. Mahoney
- Allen Institute for Brain Science, Seattle, WA, USA
- Yoshiko Kojima
- Washington National Primate Research Center, University of Washington, Seattle, WA, USA
- Yi Ding
- Allen Institute for Brain Science, Seattle, WA, USA
- Saroja Somasundaram
- Allen Institute for Brain Science, Seattle, WA, USA
- Jeremy A. Miller
- Allen Institute for Brain Science, Seattle, WA, USA
- Brian E. Kalmbach
- Allen Institute for Brain Science, Seattle, WA, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA
- Cristina Radaelli
- Allen Institute for Brain Science, Seattle, WA, USA
- Bryan B. Gore
- Allen Institute for Brain Science, Seattle, WA, USA
- Natalie Weed
- Allen Institute for Brain Science, Seattle, WA, USA
- Victoria Omstead
- Allen Institute for Brain Science, Seattle, WA, USA
- Yemeserach Bishaw
- Allen Institute for Brain Science, Seattle, WA, USA
- Nadiya V. Shapovalova
- Allen Institute for Brain Science, Seattle, WA, USA
- Refugio A. Martinez
- Allen Institute for Brain Science, Seattle, WA, USA
- Olivia Fong
- Allen Institute for Brain Science, Seattle, WA, USA
- Shenqin Yao
- Allen Institute for Brain Science, Seattle, WA, USA
- Marty Mortrud
- Allen Institute for Brain Science, Seattle, WA, USA
- Peter Chong
- Allen Institute for Brain Science, Seattle, WA, USA
- Luke Loftus
- Allen Institute for Brain Science, Seattle, WA, USA
- Darren Bertagnolli
- Allen Institute for Brain Science, Seattle, WA, USA
- Jeff Goldy
- Allen Institute for Brain Science, Seattle, WA, USA
- Tamara Casper
- Allen Institute for Brain Science, Seattle, WA, USA
- Nick Dee
- Allen Institute for Brain Science, Seattle, WA, USA
- Ximena Opitz-Araya
- Allen Institute for Brain Science, Seattle, WA, USA
- Ali Cetin
- Department of Biology and Applied Physics, Stanford University, Stanford, CA, USA
- Kimberly A. Smith
- Allen Institute for Brain Science, Seattle, WA, USA
- Ryder P. Gwinn
- Epilepsy Surgery and Functional Neurosurgery, Swedish Neuroscience Institute, Seattle, WA, USA
- Charles Cobbs
- The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
- Andrew L. Ko
- Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA; Regional Epilepsy Center, Harborview Medical Center, Seattle, WA, USA
- Jeffrey G. Ojemann
- Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA; Regional Epilepsy Center, Harborview Medical Center, Seattle, WA, USA
- C. Dirk Keene
- Department of Pathology, University of Washington, Seattle, WA, USA
- Daniel L. Silbergeld
- Department of Neurological Surgery and Alvord Brain Tumor Center, University of Washington, Seattle, WA, USA
- Susan M. Sunkin
- Allen Institute for Brain Science, Seattle, WA, USA
- Viviana Gradinaru
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Gregory D. Horwitz
- Washington National Primate Research Center, University of Washington, Seattle, WA, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA
- Hongkui Zeng
- Allen Institute for Brain Science, Seattle, WA, USA
- Bosiljka Tasic
- Allen Institute for Brain Science, Seattle, WA, USA
- Ed S. Lein
- Allen Institute for Brain Science, Seattle, WA, USA; Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA; Regional Epilepsy Center, Harborview Medical Center, Seattle, WA, USA
- Jonathan T. Ting
- Allen Institute for Brain Science, Seattle, WA, USA; Washington National Primate Research Center, University of Washington, Seattle, WA, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA; Corresponding author
- Boaz P. Levi
- Allen Institute for Brain Science, Seattle, WA, USA; Corresponding author
- Journal volume & issue
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Vol. 34,
no. 13
p. 108754
Abstract
Summary: Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection of Parvalbumin (PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primate neocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools.
