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Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

View ORCID ProfileRuilin Tian, Anthony Abarientos, Jason Hong, Sayed Hadi Hashemi, Rui Yan, Mike A. Nalls, Andrew B. Singleton, View ORCID ProfileKe Xu, Faraz Faghri, View ORCID ProfileMartin Kampmann
doi: https://doi.org/10.1101/2020.06.27.175679
Ruilin Tian
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Biophysics Graduate Program, University of California, San Francisco, San Francisco, CA, USA
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  • For correspondence: ruilin.tian@ucsf.edu martin.kampmann@ucsf.edu
Anthony Abarientos
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
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Jason Hong
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
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Sayed Hadi Hashemi
3Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Rui Yan
4Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
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Mike A. Nalls
5Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
6Data Tecnica International, LLC, Glen Echo, MD, USA
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Andrew B. Singleton
5Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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Ke Xu
4Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
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Faraz Faghri
3Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA
5Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
6Data Tecnica International, LLC, Glen Echo, MD, USA
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Martin Kampmann
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
7Chan Zuckerberg Biohub, San Francisco, CA, USA
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  • ORCID record for Martin Kampmann
  • For correspondence: ruilin.tian@ucsf.edu martin.kampmann@ucsf.edu
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Abstract

Single-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here, we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons. We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons following perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.

Competing Interest Statement

M.K. has filed a patent application related to CRISPRi and CRISPRa screening (PCT/US15/40449) and serves on the Scientific Advisory Board of Engine Biosciences and Casma Therapeutics.

Footnotes

  • Minor updates to Figures, references

  • https://crisprbrain.org

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 22, 2020.
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Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Ruilin Tian, Anthony Abarientos, Jason Hong, Sayed Hadi Hashemi, Rui Yan, Mike A. Nalls, Andrew B. Singleton, Ke Xu, Faraz Faghri, Martin Kampmann
bioRxiv 2020.06.27.175679; doi: https://doi.org/10.1101/2020.06.27.175679
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Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Ruilin Tian, Anthony Abarientos, Jason Hong, Sayed Hadi Hashemi, Rui Yan, Mike A. Nalls, Andrew B. Singleton, Ke Xu, Faraz Faghri, Martin Kampmann
bioRxiv 2020.06.27.175679; doi: https://doi.org/10.1101/2020.06.27.175679

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