Open AccessGenome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Author(s) -
Ruilin Tian,
Anthony Abarientos,
Jin-Hyuk Hong,
Seyed Mohammad Hashemi,
Rui Yan,
Nina M. Dräger,
Kun Leng,
Mike A. Nalls,
Andrew Singleton,
Ke Xu,
Faraz Faghri,
Martin Kampmann
Publication year - 2021
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-021-00862-0
Subject(s) - biology , crispr , transcriptome , gene , cell type , neurodegeneration , genome , genome editing , functional genomics , gene knockdown , microbiology and biotechnology , computational biology , cell , genomics , genetics , gene expression , disease , medicine , pathology
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 after 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.