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Series GSE252003 Query DataSets for GSE252003
Status Public on May 10, 2024
Title Cryptic splicing mediates genetic and therapeutic perturbation of human gene expression levels [Cut&Tag]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing “unproductive” transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS-NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared to prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of all transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Employing the splice-switching drug risdiplam to manipulate AS at hundreds of genes, we find that ~3/4 of drug-induced isoforms are targeted by NMD, suggesting that most aberrant splicing influences expression levels. Our findings suggest much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome.
 
Overall design CUT&Tag was performed as described in protocol DOI: dx.doi.org/10.17504/protocols.io.z6hf9b6 using 14 cycles instead of 13 to ensure we had enough DNA material to sequence.
 
Contributor(s) Fair BJ, Buen Abad Najar CF, Li YI
Citation(s) 39223315
BioProject PRJNA1021544
Submission date Dec 26, 2023
Last update date Oct 08, 2024
Contact name Carlos F Buen Abad Najar
E-mail(s) cnajar@uchicago.edu
Organization name University of Chicago
Department Medicine
Lab The Li lab
Street address 920 E 58th St
City Chicago
State/province Illinois
ZIP/Postal code 60637
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (93)
GSM7991205 H3K36ME3 Cut&Tag of LCLs, NA18486
GSM7991206 H3K36ME3 Cut&Tag of LCLs, NA18497
GSM7991207 H3K36ME3 Cut&Tag of LCLs, NA18498
This SubSeries is part of SuperSeries:
GSE252006 Global impact of unproductive splicing on human gene expression.

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Supplementary file Size Download File type/resource
GSE252003_H3K36ME3.counts.tab.gz 2.3 Mb (ftp)(http) TAB
GSE252003_H3K36ME3.qqnorm.tab.gz 4.1 Mb (ftp)(http) TAB
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