Project description:Long interspersed element-1 (L1) retrotransposons constitute the largest transposable element (TE) family in mammalian genomes and contribute prominently to inter- and intra-individual genetic variation. Although most L1 elements are inactive, some evolutionary younger insertions remain intact and genetically competent for transcription and occasionally retrotransposition. Despite being generally more abundant in gene-poor regions, intact or full-length L1s (FL-L1) are also enriched around specific classes of genes and on the X chromosome. How proximal FL-L1 may affect nearby gene expression remains unclear. Here, we examine this systematically using engineered mouse embryonic stem cells (ESCs) in which expression of one active L1 subfamily is perturbed. We found that FL-L1 activation leads to the misregulation of ~1,024 genes, whereas FL-L1 repression affects ~81 genes. In most cases, misexpressed genes contain an intronic FL-L1 or lie near a FL-L1 (<260 kb). Gene ontology analysis shows that upon L1 activation, upregulated genes are enriched for neuronal function-related terms, suggesting that some L1 elements may have evolved to control neuronal gene networks. These results illustrate the cis-regulatory potential of FL-L1 elements and suggest a broader role for L1s than originally anticipated.
Project description:Circular RNAs (circRNAs) have been found abundantly expressed in cancer. Their resistance to exonucleases enables them to have potentially stable interactions with with different types of biomolecules. Alternative splicing can create different circRNA isoforms that have different sequences and unequal interaction potentials. The study of circRNA function thus requires knowledge of complete circRNA sequences. Here we describe psirc, a method that can identify full-length circRNA isoforms and quantify their expression levels using RNA sequencing data. We confirm the effectiveness and computational efficiency of psirc using both simulated and actual experimental data. Applying psirc on transcriptome profiles from nasopharyngeal carcinoma and normal nasopharynx samples, we discovered circRNA isoforms differentially expressed between the two groups. Compared to the assumed circular isoforms derived from linear transcript annotations, some of the alternatively spliced circular isoforms have 100 times higher expression and contain fewer microRNA response elements, demonstrating the importance of quantifying full-length circRNA isoforms.
Project description:Androgen Receptor (AR) variants (AR-V) drive prostate cancer (PCa) resistance to first and second-generation therapies targeting endocrine regulation of AR. To understand the sets of genomic targets of full-length AR vs. AR-Vs, we conducted genome-wide ChIP-seq using isogenic pairs of genome engineering cell lines expressing either ARv567es (R1-D567) or full-length AR (R1-AD1). Our data demonstrate that androgen-activated full-length AR and AR-Vs both bind to similar genomic targets, which are enriched for high affinity androgen response elements (AREs). Overall, this study demonstrates that AR-Vs restore the broad AR cistrome that is otherwise lost during endocrine-targeted therapy.