Publication

Statistical learning quantifies transposable element-mediated cis-regulation

Didier Trono, Evaristo Jose Planet Letschert, Julien Léonard Duc, Cyril David Son-Tuyên Pulver, Alexandre Coudray, Julien Paul André Pontis, Delphine Yvette L Grun, Shaoline Sheppard, Raphaël Gérard Théodore Michel Marie de Deloÿe et Fourcade de Fondeville
2023
Journal Articles

Abstract

Background: Transposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryo- genesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription fac- tors (TFs). Results: Here, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 500 kb of promot- ers. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryo- genesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differ- ences in histone marks. Conclusion: Our results suggest that TE-embedded CREs contribute to gene regula- tion during and beyond gastrulation. On a methodological level, we provide a statisti- cal tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitat- ing the study of TEs in the next-generation sequencing era.

Official source

Abstract

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Ontological neighbourhood

Biology

Genetics: Molecular genetics

Related concepts (32)

Gene expression

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA.

Regulation of gene expression

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein.

Cis-regulatory element

Cis-regulatory elements (CREs) or Cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphogenesis, the development of anatomy, and other aspects of embryonic development, studied in evolutionary developmental biology. CREs are found in the vicinity of the genes that they regulate. CREs typically regulate gene transcription by binding to transcription factors.

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