Psalm Haseley

Landscape of somatic retrotransposition in human cancers.

Movement in the Cancer Genome Transposable elements are genetic sequences that can replicate and move within the genome. The factors that make an element mobile are unknown but are generally considered rare in mammals. Lee et al. (p. 967, published online 28 June) analyzed five cancer types occurring among several individuals and found that three types of epithelial tumors exhibited high rates of element movement relative to brain and blood cancers. Furthermore, these somatically acquired, tumor-specific elements targeted genes in colorectal cancer that, when disrupted, impact gene expression and thus may be a factor in the progression of the cancers. Whole-genome sequencing provides evidence for somatic insertions in colorectal, prostate, and ovarian cancers. Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.

Comparative analysis of metazoan chromatin organization

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal ‘arms’, and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

Diverse Mechanisms of Somatic Structural Variations in Human Cancer Genomes

Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ∼20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements.Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ~20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements.

A Wnt-Bmp Feedback Circuit Controls Intertissue Signaling Dynamics in Tooth Organogenesis

Computational and genetic analyses reveal a key circuit involving Wnt and Bmp in developing teeth in mice. A Toothsome Circuit Interactions between two different types of tissue, epithelium and mesenchyme, play important roles in development and cancer. Tooth development is a system for studying epithelial-mesenchymal interactions that is amenable to experimental manipulation. O’Connell et al. performed gene expression profiling of developing molar dental tissues in mice and computational analyses to construct a gene regulatory network that identified a key feedback circuit mediated by diffusible signaling molecules of the Wnt and Bmp families. This circuit controls the production of signaling molecules in other pathways and is self-sustaining. The authors validated their circuit in mice with mutations expected to disrupt the Wnt-Bmp signaling pathways. Similar feedback circuits may also operate in epithelial-mesenchymal interactions in other developing organs or in tumors. Many vertebrate organs form through the sequential and reciprocal exchange of signaling molecules between juxtaposed epithelial and mesenchymal tissues. We undertook a systems biology approach that combined the generation and analysis of large-scale spatiotemporal gene expression data with mouse genetic experiments to gain insight into the mechanisms that control epithelial-mesenchymal signaling interactions in the developing mouse molar tooth. We showed that the shift in instructive signaling potential from dental epithelium to dental mesenchyme was accompanied by temporally coordinated genome-wide changes in gene expression in both compartments. To identify the mechanism responsible, we developed a probabilistic technique that integrates regulatory evidence from gene expression data and from the literature to reconstruct a gene regulatory network for the epithelial and mesenchymal compartments in early tooth development. By integrating these epithelial and mesenchymal gene regulatory networks through the action of diffusible extracellular signaling molecules, we identified a key epithelial-mesenchymal intertissue Wnt-Bmp (bone morphogenetic protein) feedback circuit. We then validated this circuit in vivo with compound genetic mutations in mice that disrupted this circuit. Moreover, mathematical modeling demonstrated that the structure of the circuit accounted for the observed reciprocal signaling dynamics. Thus, we have identified a critical signaling circuit that controls the coordinated genome-wide expression changes and reciprocal signaling molecule dynamics that occur in interacting epithelial and mesenchymal compartments during organogenesis.

Analysis of somatic retrotransposition in human cancers

Background Close to half of the human genome is derived from transposable elements (TEs), and some TE families continue to generate new insertions through RNA-mediated mechanisms. Due to its mutagenic potential, such retrotransposition is normally suppressed by epigenetic and post-transcriptional mechanisms. However, the epigenetic and regulatory disruptions commonly observed in cancers may allow for TE activation, and a few examples have been reported in lung and colon cancer previously.