PreprintCited by 177Genomics and Chromatin DynamicsGene Regulatory Network AnalysisRNA and protein synthesis mechanisms

Gene expression is encoded in all parts of a co-evolving interacting gene regulatory structure

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Zrimec, Jan, Buric, Filip, Muhammad, Azam Sheikh, Chen, Rhongzen, Verendel, Vilhelm, Töpel, Mats, Zelezniak, Aleksej·2019·Nature Communications

Preprint — published as 10.1038/s41467-020-19921-4 · Paper page

Abstract

Understanding the genetic regulatory code that governs gene expression is a primary, yet challenging aspiration in molecular biology that opens up possibilities to cure human diseases and solve biotechnology problems. However, the fundamental question of how each of the individual coding and non-coding regions of the gene regulatory structure interact and contribute to the mRNA expression levels remains unanswered. Considering that all the information for gene expression regulation is already present in living cells, here we applied deep learning on over 20,000 mRNA datasets in 7 model organisms ranging from bacteria to Human. We show that in all organisms, mRNA abundance can be predicted directly from the DNA sequence with high accuracy, demonstrating that up to 82% of the variation of gene expression levels is encoded in the gene regulatory structure. Coding and non-coding regions carry both overlapping and orthogonal information and additively contribute to gene expression levels. By searching for DNA regulatory motifs present across the whole gene regulatory structure, we discover that motif interactions can regulate gene expression levels in a range of over three orders of magnitude. The uncovered co-evolution of coding and non-coding regions challenges the current paradigm that single motifs or regions are solely responsible for gene expression levels. Instead, we show that the correct combination of all regulatory regions must be established in order to accurately control gene expression levels. Therefore, the holistic system that spans the entire gene regulatory structure is required to analyse, understand, and design any future gene expression systems.

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Authors
Zrimec, J., Buric, F., Muhammad, A. S., Chen, R., Verendel, V., Töpel, M., & Zelezniak, A.
Affiliations
  • Chalmers University of Technology (SE)
  • University of Gothenburg (SE)
  • Science for Life Laboratory (SE)
Corresponding author
Zelezniak, Aleksej
Venue
Nature Communications
Publisher
openRxiv
Published
2019-10-04
Volume
11
Issue
1
Pages
6141-6141
ISSN
2041-1723 (ISSN-L)
OpenAlex
W3108101741
Cited by
173
References
154
Citations by year
2026: 18 · 2025: 35 · 2024: 42 · 2023: 28 · 2022: 27 · 2021: 21 · 2020: 2
FWCI
6.33
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Chalmers Research (Chalmers University of Technology) (submittedVersion)
Funders
  • Nvidia
  • European Commission (722287)
  • Chalmers Tekniska Högskola
  • Science for Life Laboratory
  • Novo Nordisk Fonden (NNF10CC1016517)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
gene expression regulation, mRNA levels, DNA sequences, regulatory motifs, coevolution, non-coding regions, coding sequences, deep learning, transcriptome, model organisms
MeSH terms
Deep Learning, Animals, Bacteria, Base Sequence, Drosophila melanogaster, Gene Expression Regulation, Humans, Regulatory Sequences, Nucleic Acid, RNA, Messenger, Saccharomyces cerevisiae, Evolution, Molecular, Mice

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