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Functional Enhancer Elements Drive Subclass-Selective Expression from Mouse to Primate Neocortex

93 Pages Posted: 20 May 2020 Sneak Peek Status: Under Review

See all articles by John K. Mich

John K. Mich

Allen Institute for Brain Science

Lucas T. Graybuck

Allen Institute for Brain Science

Erik Hess

Allen Institute for Brain Science

Joseph Mahoney

Allen Institute for Brain Science

Yoshiko Kojima

University of Washington - Washington National Primate Research Center

Yi Ding

Allen Institute for Brain Science

Saroja Somasundaram

Allen Institute for Brain Science

Jeremy A. Miller

Allen Institute for Brain Science

Natalie Weed

Allen Institute for Brain Science

Victoria Omstead

Allen Institute for Brain Science

Yemeserach Bishaw

Allen Institute for Brain Science

Nadiya Shapovalova

Allen Institute for Brain Science

Refugio Martinez

University of Washington - Department of Pathology

Olivia Fong

Allen Institute for Brain Science

Shenqin Yao

Allen Institute for Brain Science

Marty Mortrud

Allen Institute for Brain Science

Peter Chong

Allen Institute for Brain Science

Luke Loftus

Allen Institute for Brain Science

Darren Bertagnolli

Allen Institute for Brain Science

Jeff Goldy

Allen Institute for Brain Science

Tamara Casper

Allen Institute for Brain Science

Nick Dee

Allen Institute for Brain Science

Ximena Opitz-Araya

Allen Institute for Brain Science

Ali Cetin

Stanford University - Department of Biology

Kimberly A. Smith

Allen Institute for Brain Science

Ryder P. Gwinn

Swedish Neuroscience Institute - Department of Epilepsy Surgery and Functional Neurosurgery

Charles Cobbs

Swedish Neuroscience Institute - The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment

Andrew L. Ko

University of Washington - Department of Neurological Surgery

Jeffrey G. Ojemann

Seattle Children's Hospital; University of Washington - Department of Neurological Surgery

C. Dirk Keene

University of Washington - Department of Pathology

Daniel L. Silbergeld

University of Washington - Department of Neurological Surgery

Susan M. Sunkin

Allen Institute for Brain Science

Viviana Gradinaru

California Institute of Technology - Division of Biology and Biological Engineering

Gregory D. Horwitz

University of Washington - Washington National Primate Research Center

Hongkui Zeng

Allen Institute for Brain Science

Bosiljka Tasic

Allen Institute for Brain Science

Ed Lein

Allen Institute for Brain Science

Jonathan Ting

Allen Institute for Brain Science

Boaz Levi

Allen Institute for Brain Science

More...

Abstract

Viral genetic tools to target specific brain cell types in humans and nongenetic model organisms will transform basic neuroscience and targeted gene therapy. Here we used comparative epigenetics to identify thousands of human neuronal subclass-specific putative enhancers to regulate viral tools, and 34% of these were conserved in mouse. We established an AAV platform to evaluate cellular specificity of functional enhancers by multiplexed fluorescent in situ hybridization (FISH) and single cell RNA sequencing. Initial testing in mouse neocortex yields a functional enhancer discovery success rate of over 30%. We identify enhancers with specificity for excitatory and inhibitory classes and subclasses including PVALB, LAMP5, and VIP/LAMP5 cells, some of which maintain specificity in vivo or ex vivo in monkey and human neocortex. Finally, functional enhancers can be proximal or distal to cellular marker genes, conserved or divergent across species, and could yield brain-wide specificity greater than the most selective marker genes.

Keywords: Human, macaque, brain cell types, epigenetics, enhancers, AAVs, neocortex, reporters, genetic tools, ex vivo brain slice, ATAC-seq, RNA-seq, Parvalbumin

Suggested Citation

Mich, John K. and Graybuck, Lucas T. and Hess, Erik and Mahoney, Joseph and Kojima, Yoshiko and Ding, Yi and Somasundaram, Saroja and Miller, Jeremy A. and Weed, Natalie and Omstead, Victoria and Bishaw, Yemeserach and Shapovalova, Nadiya and Martinez, Refugio and Fong, Olivia and Yao, Shenqin and Mortrud, Marty and Chong, Peter and Loftus, Luke and Bertagnolli, Darren and Goldy, Jeff and Casper, Tamara and Dee, Nick and Opitz-Araya, Ximena and Cetin, Ali and Smith, Kimberly A. and Gwinn, Ryder P. and Cobbs, Charles and Ko, Andrew L. and Ojemann, Jeffrey G. and Keene, C. Dirk and Silbergeld, Daniel L. and Sunkin, Susan M. and Gradinaru, Viviana and Horwitz, Gregory D. and Zeng, Hongkui and Tasic, Bosiljka and Lein, Ed and Ting, Jonathan and Levi, Boaz, Functional Enhancer Elements Drive Subclass-Selective Expression from Mouse to Primate Neocortex. Available at SSRN: https://ssrn.com/abstract=3584741 or http://dx.doi.org/10.2139/ssrn.3584741
This is a paper under consideration at Cell Press and has not been peer-reviewed.

John K. Mich

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Lucas T. Graybuck

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Erik Hess

Allen Institute for Brain Science

Joseph Mahoney

Allen Institute for Brain Science

Yoshiko Kojima

University of Washington - Washington National Primate Research Center

Seattle, WA 98195
United States

Yi Ding

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Saroja Somasundaram

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Jeremy A. Miller

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Natalie Weed

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Victoria Omstead

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Yemeserach Bishaw

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Nadiya Shapovalova

Allen Institute for Brain Science

Refugio Martinez

University of Washington - Department of Pathology

Seattle, WA 98115
United States

Olivia Fong

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Shenqin Yao

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Marty Mortrud

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Peter Chong

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Luke Loftus

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Darren Bertagnolli

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Jeff Goldy

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Tamara Casper

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Nick Dee

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Ximena Opitz-Araya

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Ali Cetin

Stanford University - Department of Biology

Stanford, CA 94305
United States

Kimberly A. Smith

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Ryder P. Gwinn

Swedish Neuroscience Institute - Department of Epilepsy Surgery and Functional Neurosurgery

550 17th Avenue Suite 500
Seattle, WA 98122
United States

Charles Cobbs

Swedish Neuroscience Institute - The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment

550 17th Avenue Suite 500
Seattle, WA 98122
United States

Andrew L. Ko

University of Washington - Department of Neurological Surgery

Seattle, WA 98195
United States

Jeffrey G. Ojemann

Seattle Children's Hospital

4800 Sand Point Way NE
Seattle, WA 98105
United States

University of Washington - Department of Neurological Surgery

Seattle, WA 98195
United States

C. Dirk Keene

University of Washington - Department of Pathology

Seattle, WA 98115
United States

Daniel L. Silbergeld

University of Washington - Department of Neurological Surgery

Seattle, WA 98195
United States

Susan M. Sunkin

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Viviana Gradinaru

California Institute of Technology - Division of Biology and Biological Engineering

Pasadena, CA 91125
United States

Gregory D. Horwitz

University of Washington - Washington National Primate Research Center

Seattle, WA 98195
United States

Hongkui Zeng

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Bosiljka Tasic

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Ed Lein

Allen Institute for Brain Science

615 Westlake Ave N
Seattle, WA 98109
United States

Jonathan Ting

Allen Institute for Brain Science

Boaz Levi (Contact Author)

Allen Institute for Brain Science ( email )

615 Westlake Ave N
Seattle, WA 98109
United States

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