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:In mammals, extensive chromatin reorganization is essential for reprogramming terminally committed gametes to a totipotent state during preimplantation development. However, the global chromatin landscape and its dynamics in this period remain unexplored. Here we report a genome-wide map of accessible chromatin in mouse preimplantation embryos using an improved assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) approach with CRISPR/Cas9-assisted mitochondrial DNA depletion. We show that despite extensive parental asymmetry in DNA methylomes, the chromatin accessibility between the parental genomes is globally comparable after major zygotic genome activation (ZGA). Accessible chromatin in early embryos is widely shaped by transposable elements and overlaps extensively with putative cis-regulatory sequences. Unexpectedly, accessible chromatin is also found near the transcription end sites of active genes. By integrating the maps of cis-regulatory elements and single-cell transcriptomes, we construct the regulatory network of early development, which helps to identify the key modulators for lineage specification. Finally, we find that the activities of cis-regulatory elements and their associated open chromatin diminished before major ZGA. Surprisingly, we observed many loci showing non-canonical, large open chromatin domains over the entire transcribed units in minor ZGA, supporting the presence of an unusually permissive chromatin state. Together, these data reveal a unique spatiotemporal chromatin configuration that accompanies early mammalian development. Mouse preimplantation embryos were obtained from crosses of C57BL/6N and DBA/2N. ATAC-seq was performed in these embryos at various stages in preimplantation development.
Project description:In mammals, extensive chromatin reorganization is essential for reprogramming terminally committed gametes to a totipotent state during preimplantation development. However, the global chromatin landscape and its dynamics in this period remain unexplored. Here we report a genome-wide map of accessible chromatin in mouse preimplantation embryos using an improved assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) approach with CRISPR/Cas9-assisted mitochondrial DNA depletion. We show that despite extensive parental asymmetry in DNA methylomes, the chromatin accessibility between the parental genomes is globally comparable after major zygotic genome activation (ZGA). Accessible chromatin in early embryos is widely shaped by transposable elements and overlaps extensively with putative cis-regulatory sequences. Unexpectedly, accessible chromatin is also found near the transcription end sites of active genes. By integrating the maps of cis-regulatory elements and single-cell transcriptomes, we construct the regulatory network of early development, which helps to identify the key modulators for lineage specification. Finally, we find that the activities of cis-regulatory elements and their associated open chromatin diminished before major ZGA. Surprisingly, we observed many loci showing non-canonical, large open chromatin domains over the entire transcribed units in minor ZGA, supporting the presence of an unusually permissive chromatin state. Together, these data reveal a unique spatiotemporal chromatin configuration that accompanies early mammalian development. Mouse 2-cell embryos were obtained from crosses of C57BL/6N x PWK for ChIP-seq samples.
Project description:Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy