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Roles of transposable elements in the regulation of mammalian transcription

Nature Reviews Molecular Cell Biology volume 23, pages 481–497 (2022)Cite this article

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Abstract

Transposable elements (TEs) comprise about half of the mammalian genome. TEs often contain sequences capable of recruiting the host transcription machinery, which they use to express their own products and promote transposition. However, the regulatory sequences carried by TEs may affect host transcription long after the TEs have lost the ability to transpose. Recent advances in genome analysis and engineering have facilitated systematic interrogation of the regulatory activities of TEs. In this Review, we discuss diverse mechanisms by which TEs contribute to transcription regulation. Notably, TEs can donate enhancer and promoter sequences that influence the expression of host genes, modify 3D chromatin architecture and give rise to novel regulatory genes, including non-coding RNAs and transcription factors. We discuss how TEs spur regulatory evolution and facilitate the emergence of genetic novelties in mammalian physiology and development. By virtue of their repetitive and interspersed nature, TEs offer unique opportunities to dissect the effects of mutation and genomic context on the function and evolution of cis-regulatory elements. We argue that TE-centric studies hold the key to unlocking general principles of transcription regulation and evolution.

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Fig. 1: Major types of TEs in mammalian genomes.
Fig. 2: Overview of mechanisms by which TEs influence host transcription regulation.
Fig. 3: Examples of families of TEs in humans and mice that may have cis-regulatory functions based on the binding of specific TFs or on functional experiments.
Fig. 4: Transposable element insertional polymorphisms that drive cis-regulatory changes and their phenotypic association in GWAS.
Fig. 5: Use of TEs as a model system for studying transcription regulation.

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Acknowledgements

We apologize to our colleagues whose work we were unable to cite due to space limitations. This work was supported by awards R35-GM122550, U01-HG009391 and R01-CA260691 from the National Institutes of Health to C.F., and R35-GM131757 and HHMI investigator award to J.W. J.J. was supported by NHGRI fellowship F31-HG010820. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.F. was funded by an EMBO long-term fellowship and a Cancer Research Institute/Bristol-Myers Squibb postdoctoral fellowship.

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  1. These authors contributed equally: Raquel Fueyo, Julius Judd.

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  1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA

    Raquel Fueyo & Joanna Wysocka

  2. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA

    Julius Judd & Cedric Feschotte

  3. Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA

    Joanna Wysocka

  4. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Joanna Wysocka

  5. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA

    Joanna Wysocka

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Glossary

Co-opted

Co-opted or exapted refers to the process by which transposable element (TE) sequences are repurposed for host function. Classically, this term implies that the process conferred adaptive changes that increased organismal fitness. In the context of gene regulation, the term is also used to describe the process by which TEs give rise to novel cis-regulatory elements that cause demonstrable changes in host gene expression.

Gene-battery model

Theory developed by Britten and Davidson postulating that repetitive sequences are a driver of the evolution of protein expression control with a limited number of effectors.

Chimeric and alternative transcripts

Transcripts that result from joining by splicing of RNAs that are not part of the same region of origin. They may comprise exons of different genes or combinations of sequences of TE and non-TE origin.

Methyl-CpG sites

The cytosine in 5′-CpG-3′ dinucleotides (C-phosphate-G) can be methylated to form 5-methylcytosine, which frequently triggers a C-to-T mutation through deamination.

Topologically associating domain

(TAD). Large architectural domains of chromatin demarcated by insulator proteins that generally restrict the space in which three-dimensional DNA contacts and enhancer–promoter interactions are favoured.

Chromatin loop domain

Folding of chromatin that causes two regions of the genome that are separated by (a large) linear space along the DNA to come into close three-dimensional proximity.

KRAB domains

Repressive transcription factor domain, characterizing KRAB containing zinc-finger repressor proteins.

Metastable epialleles

Alleles that are differentially epigenetically regulated and maintained throughout the organism’s lifetime and, in some cases, also across generations. They typically arise due to the variable levels of DNA methylation established during early development and can respond to environmental stressors and potentially drive phenotypic variation.

Trans-chromosomic mESCs

Mouse embryonic stem cell (mESC) clones to which a human chromosome has been transferred, resulting in aneuploid cells in which the effects of a non-primate cellular context on a primate chromosome can be assayed.

Position-effect variegation

Phenomenon that defines the distinct expression levels that a gene or transgene exhibits when located at different positions in the genome, usually in correlation with the activated or repressed status of the neighbouring chromatin.

TE insertion polymorphism

A TE insertion allele that is not yet fixed but segregating in the population; emerges from transpositions that occur in the germline and may be transmitted to the offspring, thereby increasing TE frequency in the population.

Expression quantitative trait loci

Loci that explain expression variation among individuals in a population.

Genome-wide association studies

(GWAS). A population genetics method of linking genetic variants present within the population with various traits and diseases.

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Fueyo, R., Judd, J., Feschotte, C. et al. Roles of transposable elements in the regulation of mammalian transcription. Nat Rev Mol Cell Biol 23, 481–497 (2022). https://doi.org/10.1038/s41580-022-00457-y

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