Biology subjects

Feschotte, C.

Publications and source records attributed to Feschotte, C..

29 records · Page 2Linked to original sources

bioRxiv2020

Evolution of mouse circadian enhancers from transposable elements

BackgroundTransposable elements are increasingly recognized as a source of cis-regulatory variation. Previous studies have revealed that transposons are often bound by transcription factors and some have been co-opted into functional enhancers regulating host gene expression. However, the process by which transposons mature into complex regulatory elements, like enhancers, remains poorly understood. To investigate this process, we examined the contribution of transposons to the cis-regulatory network controlling circadian gene expression in the mouse liver, a well-characterized network serving an important physiological function. ResultsChIP-seq analyses revealed that transposons and other repeats contribute ~14% of the binding sites for core circadian regulators (CRs) including BMAL1, CLOCK, PER1/2, and CRY1/2, in the mouse liver. RSINE1, an abundant murine-specific SINE, was the only transposon family enriched for CR binding sites across all datasets. Sequence analyses and reporter assays revealed that the circadian regulatory activity of RSINE1 stems from the presence of imperfect CR binding motifs in the ancestral RSINE1 sequence. These motifs matured into canonical motifs through point mutations after transposition. Furthermore, maturation occurred preferentially within elements inserted in proximity of ancestral CR binding sites. RSINE1 also acquired motifs that recruit nuclear receptors known to cooperate with CR to regulate circadian gene expression specifically in the liver. ConclusionsOur results suggest that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site. This model illuminates how transposition fuels the emergence and turnover of enhancers during mammalian evolution.

genomics↗

bioRxiv2020

Antiviral activity of a human placental protein of retroviral origin

Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by these elements protect against exogenous viruses, but this activity has not been documented in human. We report that our genome harbors a large pool of envelope-derived sequences with the potential to restrict retroviral infection. To further test this, we characterize in detail the envelope-derived protein, Suppressyn. We found that Suppressyn is expressed in preimplantation embryos and developing placenta using its ancestral retroviral promoter. Restriction assays in cell culture show that Suppressyn, and its hominoid orthologs, can restrict infection by extant mammalian type D retroviruses. Our data support a generalizable model of retroviral envelope cooption for host immunity and genome defense. SummaryWe found that the human genome expresses a vast pool of envelope sequences of retroviral origin and provide proof of principle that such proteins can restrict zoonotic viruses.

molecular biology↗

bioRxiv2020

Human Endogenous Retrovirus K Rec forms a regulatory loop with MITF that opposes the progression of melanoma to an invasive stage

The HML2 subfamily of HERV-K (henceforth HERV-K) represents the most recently endogenized retrovirus in the human genome. While the products of certain HERV-K genomic copies are expressed in normal tissues, they are upregulated in a number of pathological conditions, including various tumours. It remains unclear whether HERV-K(HML2)-encoded products overexpressed in cancer contribute to disease progression or are merely by-products of tumorigenesis. Here, we focus on the regulatory activities of the Long Terminal Repeats (LTR5_Hs) of HERV-K and on the potential role of the HERV-K-encoded Rec in melanoma. Our regulatory genomics analysis of LTR5_Hs loci indicates that Melanocyte Inducing Transcription Factor (MITF) binds to a canonical E-box motif (CA(C/T)GTG) within these elements in proliferative type of melanoma, and that depletion of MITF results in reduced HERV-K expression. In turn, experimentally depleting Rec in a proliferative melanoma cell line leads to lower mRNA levels of MITF and its predicted target genes. Furthermore, Rec knockdown leads to an upregulation of epithelial-to-mesenchymal associated genes and to an enhanced invasion phenotype of proliferative melanoma cells. Together these results suggest the existence of a regulatory loop between MITF and Rec that may modulate the transition from proliferative to invasive stages of melanoma. Because HERV-K(HML2) elements are restricted to hominoid primates, these findings might explain certain species-specific features of melanoma progression and point to some limitations of animal models in melanoma studies.

genomics↗

bioRxiv2020

A single-cell RNA expression map of human coronavirus entry factors

To predict the tropism of human coronaviruses, we profile 28 SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) using single-cell RNA-sequencing data from a wide range of healthy human tissues. SCARFs include cellular factors both facilitating and restricting viral entry. Among adult organs, enterocytes and goblet cells of the small intestine and colon, kidney proximal tubule cells, and gallbladder basal cells appear most permissive to SARS-CoV-2, consistent with clinical data. Our analysis also suggests alternate entry paths for SARS-CoV-2 infection of the lung, central nervous system, and heart. We predict spermatogonial cells and prostate endocrine cells, but not ovarian cells, to be highly permissive to SARS-CoV-2, suggesting male-specific vulnerabilities. Early stages of embryonic and placental development show a moderate risk of infection. The nasal epithelium looks like another battleground, characterized by high expression of both promoting and restricting factors and a potential age-dependent shift in SCARF expression. Lastly, SCARF expression appears broadly conserved across human, chimpanzee and macaque organs examined. Our study establishes an important resource for investigations of coronavirus biology and pathology.

systems biology↗

bioRxiv2020

Recurrent evolution of vertebrate transcription factors by transposase capture.

How genes with novel cellular functions evolve is a central biological question. Exon shuffling is one mechanism to assemble new protein architectures. Here we show that DNA transposons, which are mobile and pervasive in genomes, have provided a recurrent supply of exons and splice sites to assemble protein-coding genes in vertebrates via exon-shuffling. We find that transposase domains have been captured, primarily via alternative splicing, to form new fusion proteins at least 94 times independently over [~]350 million years of tetrapod evolution. Evolution favors fusion of transposase DNA-binding domains to host regulatory domains, especially the Kruppel-associated Box (KRAB), suggesting transposase capture frequently yields new transcriptional repressors. We show that four independently evolved KRAB-transposase fusion proteins repress gene expression in a sequence-specific fashion. Genetic knockout and rescue of the bat-specific KRABINER fusion gene in cells demonstrates that it binds its cognate transposons genome-wide and controls a vast network of genes and cis-regulatory elements. These results illustrate a powerful mechanism by which a transcription factor and its dispersed binding sites emerge at once from a transposon family. One Sentence SummaryHost-transposase fusion generates novel cellular genes, including deeply conserved and lineage specific transcription factors.

genomics↗

bioRxiv2019

RepeatModeler2: automated genomic discovery of transposable element families

The accelerating pace of genome sequencing throughout the tree of life is driving the need for improved unsupervised annotation of genome components such as transposable elements (TEs). Because the types and sequences of TEs are highly variable across species, automated TE discovery and annotation are challenging and time-consuming tasks. A critical first step is the de novo identification and accurate compilation of sequence models representing all the unique TE families dispersed in the genome. Here we introduce RepeatModeler2, a new pipeline that greatly facilitates this process. This new program brings substantial improvements over the original version of RepeatModeler, one of the most widely used tools for TE discovery. In particular, this version incorporates a module for structural discovery of complete LTR retroelements, which are widespread in eukaryotic genomes but recalcitrant to automated identification because of their size and sequence complexity. We benchmarked RepeatModeler2 on three model species with diverse TE landscapes and high-quality, manually curated TE libraries: Drosophila melanogaster (fruit fly), Danio rerio (zebrafish), and Oryza sativa (rice). In these three species, RepeatModeler2 identified approximately three times more consensus sequences matching with >95% sequence identity and sequence coverage to the manually curated sequences than the original RepeatModeler. As expected, the greatest improvement is for LTR retroelements. The program had an extremely low false positive rate when applied to simulated genomes devoid of TEs. Thus, RepeatModeler2 represents a valuable addition to the genome annotation toolkit that will enhance the identification and study of TEs in eukaryotic genome sequences. RepeatModeler2 is available as source code or a containerized package under an open license (https://github.com/Dfam-consortium/RepeatModeler, https://github.com/Dfam-consortium/TETools). SignificanceGenome sequences are being produced for more and more eukaryotic species. The bulk of these genomes is composed of parasitic, self-mobilizing transposable elements (TEs) that play important roles in organismal evolution. Thus there is a pressing need for developing software that can accurately identify the diverse set of TEs dispersed in genome sequences. Here we introduce RepeatModeler2, an easy-to-use package for the curation of reference TE libraries which can be applied to any eukaryotic species. Through several major improvements over the previous version, RepeatModeler2 is able to produce libraries that recapitulate the known composition of three model species with some of the most complex TE landscapes. Thus RepeatModeler2 will greatly enhance the discovery and annotation of TEs in genome sequences.

genomics↗

bioRxiv2019

TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data

Alu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alu are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alu and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline -- TypeTE -- which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a gold standard set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics.

bioinformatics↗

bioRxiv2019

Contribution of unfixed transposable element insertions to human regulatory variation

Thousands of unfixed transposable element (TE) insertions segregate in the human population, but little is known about their impact on genome function. Recently, a few studies associated polymorphic TE insertions to mRNA levels of adjacent genes, but the biological significance of these associations, their replicability across cell types, and the mechanisms by which they may regulate genes remain largely unknown. Here we performed a TE-expression QTL analysis of 444 lymphoblastoid cell lines and 294 induced pluripotent stem cells using a newly developed set of genotypes for 2,806 polymorphic TE insertions. We identified 211 and 324 TE-eQTL acting in cis in each respective cell type. Approximately one fourth were shared across cell types with strongly correlated effects. Furthermore, analysis of chromatin accessibility QTL in a subset of the lymphoblastoid cell lines suggests that unfixed TEs often modulate the activity of enhancers and other distal regulatory DNA elements, which tend to lose accessibility when a TE inserts within them. We also document a case of an unfixed TE likely influencing gene expression at the post-transcriptional level. Our study points to broad and diverse cis-regulatory effects of unfixed TEs in the human population and underscores their plausible contribution to phenotypic variation.

genomics↗

bioRxiv2018

Diverse endogenous retroviruses generate structural variation between human genomes via LTR recombination

Human endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences. The vast majority of HERV sequences descend from ancient retroviral families no longer capable of infection or genomic propagation. In fact, most are no longer represented by full-length proviruses but by solitary long terminal repeats (solo LTRs) that arose via non-allelic recombination events between the two LTRs of a proviral insertion. Because LTR-LTR recombination events may occur long after proviral insertion but are challenging to detect in resequencing data, we hypothesize that this mechanism produces an underappreciated amount of genomic variation in the human population. To test this idea, we develop a computational pipeline specifically designed to capture such dimorphic HERV alleles from short-read genome sequencing data. When applied to 279 individuals sequenced as part of the Simons Genome Diversity Project, the pipeline retrieves most of the dimorphic variants previously reported for the HERV-K(HML2) subfamily as well as dozens of additional candidates, including members of the HERV-H and HERV-W families. We experimentally validate several of these candidates, including the first reported instance of an unfixed HERV-W provirus. These data indicate that human proviral content exhibit more extensive interindividual variation than previously recognized. These findings have important implications for our understanding of the contribution of HERVs to human physiology and disease.

genetics↗

bioRxiv2018

The impact of endogenous retroviruses on nuclear organization and gene expression

BackgroundThe organization of chromatin in the nucleus plays an essential role in gene regulation. When considering the mammalian genome it is important to take into account that about half of the DNA is comprised of transposable elements. Given their repetitive nature, reads associated with these elements are generally discarded or randomly distributed among elements of the same type in genome-wide analyses. Thus, it is challenging to identify the activities and properties of individual transposons. As a result, we only have a partial understanding of how transposons contribute to chromatin folding and how they impact gene regulation.\n\nResultsUsing adapted PCR and Capture-based chromosome conformation capture (3C) approaches, collectively called 4Tran, we take advantage of the repetitive nature of transposons to capture interactions from multiple copies of endogenous retrovirus (ERVs) in the human and mouse genomes. With 4Tran-PCR, reads are selectively mapped to unique regions in the genome. This enables the identification of TE interaction profiles for individual ERV families and integration events specific to particular genomes. With this approach we demonstrate that transposons engage in long-range intra-chromosomal interactions guided by the separation of chromosomes into A and B compartments as well as topologically associated domains (TADs). In contrast to 4Tran-PCR, Capture-4Tran can uniquely identify both ends of an interaction that involve retroviral repeat sequences, providing a powerful tool for uncovering the individual TE insertions that interact with, and potentially regulate target genes.\n\nConclusions4Tran provides new insight into the manner in which transposons contribute to chromosome architecture and identifies target genes that transposable elements can potentially control.

genomics↗

bioRxiv2016

The hidden elasticity of avian and mammalian genomes

Genome size in mammals and birds shows remarkably little interspecific variation compared to other taxa. Yet, genome sequencing has revealed that many mammal and bird lineages have experienced differential rates of transposable element (TE) accumulation, which would be predicted to cause substantial variation in genome size between species. Thus, we hypothesize that there has been co-variation between the amount of DNA gained by transposition and lost by deletion during mammal and avian evolution, resulting in genome size homeostasis. To test this model, we develop a computational pipeline to quantify the amount of DNA gained by TE expansion and lost by deletion over the last 100 million years (My) in the lineages of 10 species of eutherian mammals and 24 species of birds. The results reveal extensive variation in the amount of DNA gained via lineage-specific transposition, but that DNA loss counteracted this expansion to various extent across lineages. Our analysis of the rate and size spectrum of deletion events implies that DNA removal in both mammals and birds has proceeded mostly through large segmental deletions (>10 kb). These findings support a unified accordion model of genome size evolution in eukaryotes whereby DNA loss counteracting TE expansion is a major determinant of genome size. Furthermore, we propose that extensive DNA loss, and not necessarily a dearth of TE activity, has been the primary force maintaining the greater genomic compaction of flying birds and bats relative to their flightless relatives.

evolutionary biology↗