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Series GSE137258 Query DataSets for GSE137258
Status Public on Jul 02, 2021
Title Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer
Organisms Homo sapiens; synthetic construct
Experiment type Expression profiling by high throughput sequencing
Summary We found in this study through targeted CRISPR-Cas9 screening of RBPs that disrupting YTHDF2-dependent degradation of its target transcripts triggers apoptosis of MYC-dependent cancer cells and tumors. Enhanced CLIP (eCLIP), m6A-sequencing (m6A-seq) and YTHDF2 knockdown followed by RNA-seq analysis of YTHDF2-m6A-mRNA interactions revealed extensive associations with mRNAs encoding MAPK pathway genes that when stabilized, induce epithelial-to-mesenchymal transition and stress-induced apoptosis. scRibo-STAMP profiling of translating mRNAs revealed global alterations in the translatome of single cells in YTHDF2-depleted solid tumors. Thus, our work highlights the therapeutic relevance of RBPs by uncovering the critical role of YTHDF2 in counteracting the global increase of mRNA synthesis in MYC-driven cancers.

Overall design We constructed and applied an RBP targeting CRISPR-Cas9 library to MYC-inducible human mammary epithelial cells 8 and 16 days after transduction by sequencing of gDNA in biological duplicate. YTHDF2 binding and m6A profiles were examined using eCLIP-seq and m6A-seq by immunoprecipitating mRNA fragments bound to either endogenous YTHDF2 or m6A antibody in biological duplicates with input controls. In addition, we examined changes in mRNA expression following depletion of YTHDF2 using two independent shRNAs in biological duplicate. Lastly, we identified translational changes in the YTHDF2-depleted solid tumors by directing C-to-U editing of translating transcripts by transducing cells with RPS2-APOBEC1 fusions prior to subcutaneous xenograft.
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Contributor(s) Einstein JM, Perelis M, Chaim IA, Nussbacher JK, Tankka AT, Yee BA, Madrigal AA, Shankar A, Yeo GW
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Submission date Sep 11, 2019
Last update date Jul 05, 2021
Contact name Gene Yeo
Organization name UCSD
Street address 2880 Torrey Pines Scenic Dr. Room 3805/Yeo Lab
City La Jolla
State/province CA
ZIP/Postal code 92037
Country USA
Platforms (3)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
GPL21616 Illumina HiSeq 4000 (synthetic construct)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (74)
GSM4073974 Plasmid_rep1_CRISPR_RBP
GSM4073975 Plasmid_rep2_CRISPR_RBP
GSM4073976 T0_rep1_CRISPR_RBP
BioProject PRJNA564948
SRA SRP221341

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource 68.5 Kb (ftp)(http) BED
GSE137258_LM2_rep1_rep2.bed.gz 666.8 Kb (ftp)(http) BED 59.3 Kb (ftp)(http) BED
GSE137258_MCF7_rep1_rep2.bed.gz 553.2 Kb (ftp)(http) BED 30.5 Kb (ftp)(http) BED
GSE137258_MDA_rep1_rep2.bed.gz 571.1 Kb (ftp)(http) BED 40.5 Kb (ftp)(http) BED
GSE137258_MYC_HMEC_MLE_day16.gene_summary.txt.gz 26.8 Kb (ftp)(http) TXT
GSE137258_MYC_HMEC_MLE_day8.gene_summary.txt.gz 27.5 Kb (ftp)(http) TXT 23.5 Kb (ftp)(http) BED
GSE137258_MYC_HMEC_TAM_rep1_rep2.bed.gz 181.6 Kb (ftp)(http) BED
GSE137258_MYC_HMEC_rep1_rep2.bed.gz 254.6 Kb (ftp)(http) BED
GSE137258_RAW.tar 3.3 Gb (http)(custom) TAR (of BW, TXT) 146.8 Kb (ftp)(http) BED
GSE137258_SKBR3_rep1_rep2.bed.gz 671.8 Kb (ftp)(http) BED
GSE137258_all.countsummary.txt.gz 673 b (ftp)(http) TXT
GSE137258_featurecounts.txt.gz 3.4 Mb (ftp)(http) TXT
GSE137258_macs2_lm2.bed12.gz 700.6 Kb (ftp)(http) BED12
GSE137258_macs2_lm2_filtered.bed12.gz 502.9 Kb (ftp)(http) BED12
GSE137258_macs2_mcf7.bed12.gz 440.8 Kb (ftp)(http) BED12
GSE137258_macs2_mcf7_filtered.bed12.gz 263.0 Kb (ftp)(http) BED12
GSE137258_macs2_mda.bed12.gz 224.6 Kb (ftp)(http) BED12
GSE137258_macs2_mda_filtered.bed12.gz 149.6 Kb (ftp)(http) BED12
GSE137258_macs2_myc_hmec.bed12.gz 527.5 Kb (ftp)(http) BED12
GSE137258_macs2_myc_hmec_filtered.bed12.gz 397.0 Kb (ftp)(http) BED12
GSE137258_macs2_myc_hmec_tam.bed12.gz 581.6 Kb (ftp)(http) BED12
GSE137258_macs2_myc_hmec_tam_filtered.bed12.gz 407.3 Kb (ftp)(http) BED12
GSE137258_macs2_skbr3.bed12.gz 341.1 Kb (ftp)(http) BED12
GSE137258_macs2_skbr3_filtered.bed12.gz 198.2 Kb (ftp)(http) BED12
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Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

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