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Cited by 27RNA Research and SplicingGenomics and Chromatin DynamicsRNA and protein synthesis mechanisms

Sequence determinants of polyadenylation-mediated regulation

Open access
Vainberg Slutskin, Ilya, Weinberger, Adina, Segal, Eran·2019·Genome Research
DOI 10.1101/gr.247312.118PMC PMC6771402
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Abstract

The cleavage and polyadenylation reaction is a crucial step in transcription termination and pre-mRNA maturation in human cells. Despite extensive research, the encoding of polyadenylation-mediated regulation of gene expression within the DNA sequence is not well understood. Here, we utilized a massively parallel reporter assay to inspect the effect of over 12,000 rationally designed polyadenylation sequences (PASs) on reporter gene expression and cleavage efficiency. We find that the PAS sequence can modulate gene expression by over five orders of magnitude. By using a uniquely designed scanning mutagenesis data set, we gain mechanistic insight into various modes of action by which the cleavage efficiency affects the sensitivity or robustness of the PAS to mutation. Furthermore, we employ motif discovery to identify both known and novel sequence motifs associated with PAS-mediated regulation. By leveraging the large scale of our data, we train a deep learning model for the highly accurate prediction of RNA levels from DNA sequence alone (R = 0.83). Moreover, we devise unique approaches for predicting exact cleavage sites for our reporter constructs and for endogenous transcripts. Taken together, our results expand our understanding of PAS-mediated regulation, and provide an unprecedented resource for analyzing and predicting PAS for regulatory genomics applications.

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  • Sequence-based models of post-transcriptional regulation rely on genome annotations and transformed measurements extracted from RNA-seq to isolate each regulatory mechanism.

    “Similarly, sequence-based models of post-transcriptional regulation rely on genome annotations and transformed measurements extracted from RNA-seq to isolate each regulatory mechanism (for example, percent spliced-in for splicing)14–23.”

    From Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation (2025) · cites this paper as [18]

    The Discussion describes sequence-based models of polyadenylation-mediated regulation, and Methods > Computational analyses describes a transformed RNA-level measurement. But Results > High-throughput measurement of expression levels and cleavage maps says the models use measurements from a designed reporter library, not genome annotations and RNA-seq-derived measurements to isolate regulatory mechanisms. The paper does not address percent spliced-in or splicing. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Vainberg Slutskin, I., Weinberger, A., & Segal, E.
Affiliations
Weizmann Institute of Science (IL)
Corresponding author
Segal, Eran
ORCID
Venue
Genome Research
Publisher
Cold Spring Harbor Laboratory
Published
2019-09-17
Volume
29
Issue
10
Pages
1635-1647
ISSN
  • 1088-9051 (ISSN-L)
  • 1549-5469
DOI
10.1101/gr.247312.118
PMC
PMC6771402
OpenAlex
W2974101135
Cited by
27
References
0
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 7
Type
posted content
Language
en
Open access
Locations
  • Genome Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • European Research Council
  • Israel Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
polyadenylation, cleavage and polyadenylation, transcription termination, gene expression regulation, massively parallel reporter assay, scanning mutagenesis, sequence motifs, cleavage site prediction, regulatory genomics
MeSH terms
Deep Learning, Gene Expression Regulation, Humans, RNA Precursors, RNA, Messenger, Mutagenesis, Genes, Reporter, 3' Untranslated Regions, Genomics, Polyadenylation, High-Throughput Nucleotide Sequencing, Transcription Termination, Genetic

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