Roles of transposable elements in the regulation of mammalian transcription

Fueyo, Raquel; Judd, Julius; Feschotte, Cédric; Wysocka, Joanna

doi:10.1038/s41580-022-00457-y

Cited by 230 publications

(212 citation statements)

References 227 publications

Supporting

Mentioning

208

Contrasting

Order By: Relevance

“…Overall, our data support a model in which heterochromatin promotes TF binding within euchromatin by restricting TF access to ERVs. Of note, the genome undergoes two major waves of developmental epigenetic reprogramming (pre-implantation development and germ cell formation) during which ERVs become extensively activated in a highly programmed manner ( 9, 27 ). These time frames are also periods of dramatic transition in gene regulatory networks and transcription programs associated with a profound cellular plasticity required for lineage specification ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…Loss of heterochromatin via acute deletion of either one of these factors leads to transcriptional derepression of specific ERV families accompanied by the accumulation of acetylation of lysine 27 on histone H3 (H3K27ac), a chromatin modification associated with active regulatory elements (2)(3)(4). Interestingly, the long terminal repeats (LTRs) of ERVs contain numerous sites for transcription factor binding and have been shown to act as enhancers for nearby genes (4)(5)(6)(7)(8)(9). Of note, individual ERV families contain hundreds to thousands of distinct copies scattered throughout the genome (10), leading to the intriguing hypothesis that global derepression of TF binding sites within ERVs may alter the stoichiometry between TFs and their euchromatic target sites, effectively competing for these factors.…”

Section: Main Textmentioning

confidence: 99%

See 1 more Smart Citation

Loss of heterochromatin at endogenous retroviruses creates competition for transcription factor binding

O’Hara

Banaszynski

2022

Preprint

View full text Add to dashboard Cite

The mammalian genome is partitioned into active and inactive regions, broadly termed euchromatin and heterochromatin, respectively. The majority of heterochromatin consists of repetitive elements, including endogenous retroviruses (ERVs). ERVs are enriched in regulatory elements containing transcription factor (TF) binding sites with individual families containing hundreds to thousands of distinct copies scattered throughout the genome. We hypothesized that epigenetic derepression of ERVs (such as that observed during early development) may alter the stoichiometry between TFs and their euchromatic target sites, with ERVs effectively competing for these factors. To test this, we modeled acute heterochromatin loss using inducible deletion of the co-repressor KAP1 in mouse embryonic stem cells (ESCs). Upon KAP1 deletion, we observe clear reductions in chromatin accessibility, histone acetylation, and TF binding at euchromatic regions. To directly test the concept of global binding site competition, we designed exogenous binding site arrays (EBSAs) to introduce upwards of 1500 copies of the OCT4 TF binding motif into ESCs. OCT4 EBSAs specifically reduce chromatin accessibility at POU family motifs and result in reduced transcription of the pluripotency machinery with subsequent differentiation. Overall, these data support a model in which heterochromatin at ERVs promotes euchromatic TF binding and transcriptional homoeostasis. We propose that regulated ERV derepression during pre-implantation may serve as a developmental siphon to weaken the robustness of ongoing transcription programs in favor of the plasticity required for cell fate specification.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Loss of heterochromatin at endogenous retroviruses creates competition for transcription factor binding

O’Hara

Banaszynski

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, multiple genes with key roles in placentation have been derived from TEs (Imakawa et al, 2015), most prominently the syncytin genes, whose products mediate cell-cell fusion to generate a syncytialised trophoblast layer that directly contacts maternal blood (Lavialle et al, 2013). Additionally, the non-coding portions of TEs (e.g., the LTRslong terminal repeats -in ERVs) have the ability to regulate gene transcription, and through this action contribute to human embryonic development (Fuentes et al, 2018;Pontis et al, 2019Pontis et al, , 2021, innate immunity (Chuong et al, 2016), the development of cancer (Jang et al, 2019), and evolution of the feto-maternal interface, amongst others (Chuong et al, 2017;Fueyo et al, 2022). TEs can recruit host transcription factors, often in a highly tissue-specific manner, and gain epigenetic hallmarks of gene regulatory activity (e.g., open chromatin, enrichment of H3K27ac), acting as transcriptional promoters or distal enhancer elements (Chuong et al, 2017;Fueyo et al, 2022;Sundaram et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Regulation of human trophoblast gene expression by endogenous retroviruses

Frost

Amante

Okae

et al. 2022

Preprint

View full text Add to dashboard Cite

The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programmes. Here, we assessed the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences, and are bound by transcription factors with key roles in placental development. Using genetic editing we demonstrated that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identified an LTR10A element that regulates ENG expression, affecting secretion of soluble ENG, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.

show abstract

“…Although the genome-wide distribution patterns of SVs and TEs seems to resemble that of SNPs, we next wanted to investigate the functional and adaptive significance of lineage-specific intergenic SVs. TEs, for example, have been suggested to be important genomic material for cis -regulatory element evolution (Branco and Chuong 2020; Pontis et al 2019; Fueyo et al 2022). To test this, we studied the genomic distribution of potential cis -regulatory elements (CREs) using Assays for Transposase-Accessible Chromatin using sequencing (ATAC-seq) (Buenrostro et al 2013).…”

Section: Resultsmentioning

confidence: 99%

A butterfly pan-genome reveals a large amount of structural variation underlies the evolution of chromatin accessibility

Ruggieri

Livraghi

Lewis

et al. 2022

Preprint

View full text Add to dashboard Cite

Despite insertions and deletions being the most common structural variants (SVs) found across genomes, not much is known about how much these SVs vary within populations and between closely related species, nor their significance in evolution. To address these questions, we characterized the evolution of indel SVs using genome assemblies of three closely related Heliconius butterfly species. Over the relatively short evolutionary timescales investigated, up to 18.0% of the genome was composed of indels between two haplotypes of an individual H. charithonia butterfly and up to 62.7% included lineage-specific SVs between the genomes of the most distant species (11 Mya). Lineage-specific sequences were mostly characterized as transposable elements (TEs) inserted at random throughout the genome and their overall distribution was similarly affected by linked selection as single nucleotide substitutions. Using chromatin accessibility profiles (i.e., ATAC-seq) of head tissue in caterpillars to identify sequences with potential cis-regulatory function, we found that out of the 31,066 identified differences in chromatin accessibility between species, 30.4% were within lineage-specific SVs and 9.4% were characterized as TE insertions. These TE insertions were localized closer to gene transcription start sites than expected at random and were enriched for several transcription factor binding site candidates with known function in neuron development in Drosophila. We also identified 24 TE insertions with head-specific chromatin accessibility. Our results show high rates of structural genome evolution that were previously overlooked in comparative genomic studies and suggest a high potential for structural variation to serve as raw material for adaptive evolution.

show abstract

Roles of transposable elements in the regulation of mammalian transcription

Cited by 230 publications

References 227 publications

Loss of heterochromatin at endogenous retroviruses creates competition for transcription factor binding

Loss of heterochromatin at endogenous retroviruses creates competition for transcription factor binding

Regulation of human trophoblast gene expression by endogenous retroviruses

A butterfly pan-genome reveals a large amount of structural variation underlies the evolution of chromatin accessibility

Contact Info

Product

Resources

About