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Epigenetic landscape and AAV targeting of human neocortical cell classes

Mich, John K. and Gradinaru, Viviana (2019) Epigenetic landscape and AAV targeting of human neocortical cell classes. . (Submitted)

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Myriad cell types comprise the human neocortex, but their roles in normal brain function and disease are largely unknown because few tools exist. To find enhancer elements useful for cell type-specific genetic tools, we examined chromatin accessibility in >2,800 high-quality single human neocortical nuclei. Accessible elements frequently are conserved in mouse (34%), often overlap with hypomethylated sites (27%), and connect cell types with neurological diseases via trait-associated SNPs. Directly testing these elements in viral vectors demonstrates functional enhancer activity with cell type specificity predicted by their chromatin accessibility patterns. In summary we present a catalog of human cell class-specific epigenetic elements, and utilize them for new species-agnostic cell type-specific viral genetic tools, which will illuminate human neuron function and drive gene therapy applications.

Item Type:Report or Paper (Discussion Paper)
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Gradinaru, Viviana0000-0001-5868-348X
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. bioRxiv preprint first posted online Feb. 19, 2019. We thank Allison Beller for assistance procuring and distributing tissue. This work is supported by NIH BRAIN Initiative award #1RF1MH114126-01 from the National Institute of Mental Health to BT, JKM, ZY, ESL, JTT, and BPL, and National Institute on Drug Abuse award #1R01DA036909-01 to LTG, HZ, and BT, and the Nancy and Buster Alvord Endowment to CDK. The content is solely the responsibility of the authors and does not necessarily represent the views of the funding agencies. In addition, we wish to thank the Allen Institute for Brain Science founder, Paul G. Allen, for his vision, encouragement and support. Author contributions: JTT, NS, EEH, TC, MK, ND, and JKM assisted on tissue handling and flow cytometry. EEH, BPL, and JKM performed ATAC-seq with assistance from DB and KAS. JKM analyzed ATAC-seq data using techniques developed by LTG and ZY, with assistance from SS, JAM, LTG, JG, and YD. EEH, JKM, and JTT performed molecular biology and design. Single cell RNA-seq was conducted by DB, KAS, and analysis by OF, JG, ZY, and BPL. JKM and JTT tested AAV vectors. RPG, CC, JGO, ALK, CDK, and DLS procured human tissue and consent. BPL, JTT, and JKM conceived of the study design. JKM wrote the manuscript and prepared figures. RDH and TEB provided human RNA-seq data. LTG and BT provided mouse ATAC-seq data. VG provided PHP.eB capsid. SMS provided program and budgetary management. HZ, ESL, BT, JTT, and BPL provided program leadership. The authors declare no outside interests. Data and materials availability: Consented data will be deposited in a public repository upon publication.
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Nancy and Buster Alvord EndowmentUNSPECIFIED
Record Number:CaltechAUTHORS:20190220-101926873
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Official Citation:Epigenetic landscape and AAV targeting of human neocortical cell classes. John K. Mich, Erik E. Hess, Lucas T. Graybuck, Saroja Somasundaram, Jeremy A. Miller, Yi Ding, Nadiya V. Shapovalova, Olivia Fong, Shenqin Yao, Marty Mortrud, Peter Chong, Darren Bertagnolli, Jeff Goldy, Tamara Casper, Matthew Kroll, Rebecca D. Hodge, Trygve E. Bakken, Zizhen Yao, Nick Dee, Ali Cetin, Kimberly A. Smith, Ryder P. Gwinn, Charles Cobbs, Andrew L. Ko, Jeffrey G. Ojemann, C. Dirk Keene, Daniel L. Silbergeld, Viviana Gradinaru, Susan M. Sunkin, Hongkui Zeng, Ed S. Lein, Bosiljka Tasic, Jonathan T.Ting, Boaz P. Levi bioRxiv 555318; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93001
Deposited By: Tony Diaz
Deposited On:20 Feb 2019 18:31
Last Modified:16 Nov 2021 16:55

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