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Quantitative dialing of gene expression via precision targeting of KRAB repressor

Matthew S. Wilken, Christie Ciarlo, Jocelynn Pearl, Elaine Schanzer, Hanna Liao, Benjamin Van Biber, Konstantin Queitsch, Jordan Bloom, Alexander Federation, Reyes Acosta, Shinny Vong, Ericka Otterman, Douglass Dunn, Hao Wang, Pavel Zrazhevskiy, Vivek Nandakumar, Daniel Bates, Richard Sandstrom, Fyodor D. Urnov, Alister Funnell, Shon Green, John A. Stamatoyannopoulos
doi: https://doi.org/10.1101/2020.02.19.956730
Matthew S. Wilken
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Christie Ciarlo
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Jocelynn Pearl
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Elaine Schanzer
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Hanna Liao
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Benjamin Van Biber
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Konstantin Queitsch
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Jordan Bloom
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Alexander Federation
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Reyes Acosta
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Shinny Vong
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Ericka Otterman
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Douglass Dunn
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Hao Wang
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Pavel Zrazhevskiy
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Vivek Nandakumar
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Daniel Bates
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Richard Sandstrom
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Fyodor D. Urnov
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Alister Funnell
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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Shon Green
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
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John A. Stamatoyannopoulos
1Altius Institute for Biomedical Sciences (Nonprofit), Seattle, WA, USA
2Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
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  • For correspondence: jstam@altius.org jstam@uw.edu
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Abstract

Human genes are regulated quantitatively, yet the ability to specify the expression level of a native gene accurately and specifically using a defined reagent has remained elusive. Here we show that precise targeting of KRAB repressive domain within regulatory DNA unlocks an endogenous quantitative ‘dial’ that can be engaged at nucleotide resolution to program expression levels across a wide physiologic range, with single-gene specificity and high reproducibly in primary cells.

Competing Interest Statement

M.S.W., C.C., S.G, A.F., F.D.U., and J.A.S. are listed as inventors on patent applications related to the subject matter of the paper; J.P. is an employee of Tune Therapeutics, a for-profit biotechnology company.

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Posted February 11, 2021.
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Quantitative dialing of gene expression via precision targeting of KRAB repressor
Matthew S. Wilken, Christie Ciarlo, Jocelynn Pearl, Elaine Schanzer, Hanna Liao, Benjamin Van Biber, Konstantin Queitsch, Jordan Bloom, Alexander Federation, Reyes Acosta, Shinny Vong, Ericka Otterman, Douglass Dunn, Hao Wang, Pavel Zrazhevskiy, Vivek Nandakumar, Daniel Bates, Richard Sandstrom, Fyodor D. Urnov, Alister Funnell, Shon Green, John A. Stamatoyannopoulos
bioRxiv 2020.02.19.956730; doi: https://doi.org/10.1101/2020.02.19.956730
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Quantitative dialing of gene expression via precision targeting of KRAB repressor
Matthew S. Wilken, Christie Ciarlo, Jocelynn Pearl, Elaine Schanzer, Hanna Liao, Benjamin Van Biber, Konstantin Queitsch, Jordan Bloom, Alexander Federation, Reyes Acosta, Shinny Vong, Ericka Otterman, Douglass Dunn, Hao Wang, Pavel Zrazhevskiy, Vivek Nandakumar, Daniel Bates, Richard Sandstrom, Fyodor D. Urnov, Alister Funnell, Shon Green, John A. Stamatoyannopoulos
bioRxiv 2020.02.19.956730; doi: https://doi.org/10.1101/2020.02.19.956730

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