TY - JOUR
T1 - Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis
T2 - Identification of MAP2K5 kinase as a potential drug target
AU - Jo, Myungjin
AU - Chung, Ah Young
AU - Yachie, Nozomu
AU - Seo, Minchul
AU - Jeon, Hyejin
AU - Nam, Youngpyo
AU - Seo, Yeojin
AU - Kim, Eunmi
AU - Zhong, Quan
AU - Vidal, Marc
AU - Park, Hae Chul
AU - Roth, Frederick P.
AU - Suk, Kyoungho
N1 - Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2015R1A2A1A10051958). H.C.P. was supported by the Basic Science Research Program through the NRF Korea funded by the Ministry of Education (NRF-2016R1D1A1B03935123). F.P.R. was supported by US National Institutes of Health (NIH) grants HG001715 and HG004233, by the Canada Excellence Research Chairs Program, and by the Krembil and Avon Foundations. N.Y. was supported by a JSPS fellowship (Research Abroad), Japan Society for the Promotion of Science, a Banting Postdoctoral Fellowship, National Sciences and Engineering Research Council of Canada, and PRESTO research grant by Japan Science and Technology Agency (JST).
PY - 2017/9
Y1 - 2017/9
N2 - To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.
AB - To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.
UR - http://www.scopus.com/inward/record.url?scp=85028753754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028753754&partnerID=8YFLogxK
U2 - 10.1101/gr.211649.116
DO - 10.1101/gr.211649.116
M3 - Article
C2 - 28596290
AN - SCOPUS:85028753754
VL - 27
SP - 1487
EP - 1500
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 9
ER -