Project description:Transposable elements hold regulatory functions to impact cell fate determination by controlling gene expression, which when altered can promote oncogenesis. Despite accounting for half of the human genome, little is known about the transcriptional mechanisms that confer regulatory properties to transposable elements in pluripotent, mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequence of H3K27ac ChIP-seq from 32 different normal cell and tissue states, we report pluripotent stem and mature cell states-specific “regulatory transposable elements”. Those specific to pluripotent stem cells are binding sites for the pluripotency factors NANOG, SOX2 and OCT4. In mature cell and tissue states, regulatory transposable elements are docking sites for lineage-specific transcription factors, such as AR and FOXA1 in benign prostate epithelium. Expanding the positional analysis to localized prostate tumors, we show how cancer cell states remaining dependent on AR share regulatory transposable elements with pluripotent stem cells. These include regulatory transposable elements, such as Tigger3a, that serve as binding sites for AR and whose regulatory functions are required for prostate cancer cell growth. Together, our results suggest that oncogenesis differs from normal cell fate determination by hijacking pluripotent stem cells regulatory transposable elements that serve as docking sites for lineage-specific transcription factors.
Project description:Pleurotus ostreatus, also known as the oyster mushroom, is an active lignin decomposer in the forests. The genomes of the monokaryotic strains PC15 and PC9 have been used to characterize the content and distribution of transposable elements. This study analyzes the impact of transposable element insertions on the global transcriptome of P. ostreatus. The transcriptome of PC15 and PC9 has been analyzed in exponential growth during submerged fermentation in malt-yeast extract-sucrose medium RNAseq of two P. ostreatus strains: PC15 and PC9
Project description:A major challenge in biology is to determine how evolutionarily novel characters originate, however, mechanistic explanations for the origin of novelties are almost completely unknown. The evolution of mammalianM-BM- pregnancy is an excellent system in which to study the origin of novelties because extant mammals preserve major stages in the transition from egg-laying to live-birth. To determine the molecular bases of this transition we characterized the pregnant/gravid uterine transcriptome from tetrapods, including species in the three major mammalian lineages, and used ancestral transcriptome reconstruction to trace the evolutionary history of uterine gene expression. We show that thousands of genes evolved endometrial expression during the origins of mammalian pregnancy, including numerous genes that mediate maternal-fetal communication and immunotolerance.Furthermore we show that thousands of regulatory elements active inM-BM- decidualized human endometrial stromal cellsM-BM- are derived from ancient mammalian transposable elements which provided binding sites for transcription factors that mediate decidualization and endometrial cell-type identity.M-BM- Our results indicate that one of the defining mammalian novelties evolved via domestication of ancient mammalian transposable elements into hormone-responsive regulatory elements throughout the genome. Examination of histone modification and DNAse hypersensitivity in decidualized dESC
Project description:The propagation of epigenetic marks has received a great deal of attention, yet the initiation of epigenetic silencing on a new transgene, virus, or transposable element remains incompletely characterized. The overlapping function of multiple silencing mechanisms has obscured this area of investigation. Here, we have revealed two broad mechanisms that are both able to initiate silencing independently: homology-based silencing and expression-dependent silencing. By transforming exogenous transposable elements into Arabidopsis, we circumvented homology-based silencing allowing us to isolate and investigate the molecular mechanism of expression-dependent silencing. We found that several small RNA-generating mechanisms all trigger de novo expression-dependent RNA-directed DNA methylation (RdDM) through RNA Polymerase V. In addition, the silencing of transposable elements fragments stalls at the RdDM phase, while full-length elements quickly progress through RdDM to maintenance methylation and heterochromatin formation. We found that there is a narrow window of time for the transition to a fully silenced state. Transformation into a mutant genotype followed by introgression into wild-type does not result in the same level of silencing as direct transformation into wild-type. This demonstrates that the genotype of transposable element insertion or transgene transformation is key for establishing the transgenerational extent of epigenetic silencing.
Project description:Cryptic promoters within transposable elements (TEs) are transcriptionally reactivated in tumors to create novel TE-gene chimeric transcripts, which can produce immunogenic antigens. We performed the most comprehensive screen to date for these TE exaptation events in 33 TCGA tumor types, 675 cancer cell lines, and 11,686 GTEx adult tissue transcriptomes and identified 1,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Resultant whole lysate and HLA-pulldown mass spectrometry data confirmed that TS-TEAs are presented on cancer cell surfaces. In addition, we highlight the tumor-specific membrane proteins transcribed from TE promoters that can expose novel epitopes on the extracellular surface of cancer cells. Here, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that can be therapeutically exploited through immunotherapy approaches.
Project description:DNA methylation and histone H1 mediate transcriptional silencing of genes and transposable elements, but how they interact is unclear. In plants and animals with mosaic genomic methylation, functionally mysterious methylation is also common within constitutively active housekeeping genes. Here we show that H1 is enriched in methylated sequences, including genes, of Arabidopsis thaliana, yet this enrichment is independent of DNA methylation. Loss of H1 disperses heterochromatin, globally alters nucleosome organization, and activates H1-bound genes, but only weakly de-represses transposable elements. However, H1 loss strongly activates transposable elements hypomethylated through mutation of DNA methyltransferase MET1. Hypomethylation of genes also activates antisense transcription, which is enhanced by H1 loss. Our results demonstrate that H1 and DNA methylation jointly maintain transcriptional homeostasis by silencing transposable elements and aberrant intragenic transcripts. Such functionality plausibly explains why DNA methylation, a well-known mutagen, has been maintained within coding sequences of crucial plant and animal genes.
Project description:Pleurotus ostreatus, also known as the oyster mushroom, is an active lignin decomposer in the forests. The genomes of the monokaryotic strains PC15 and PC9 have been used to characterize the content and distribution of transposable elements. This study analyzes the impact of transposable element insertions on the global transcriptome of P. ostreatus. The transcriptome of PC15 and PC9 has been analyzed in exponential growth during submerged fermentation in malt-yeast extract-sucrose medium