Enhancers dysfunction in the 3D genome of cancer cells

Eukaryotic genomes are spatially organized inside the cell nucleus, forming a threedimensional (3D) architecture that allows for spatial separation of nuclear processes and for controlled expression of genes required for cell identity specification and tissue homeostasis. Hence, it is of no surprise that mis-regulation of genome architecture through rearrangements of the linear genome sequence or epigenetic perturbations are often linked to aberrant gene expression programs in tumor cells. Increasing research efforts have shed light into the causes and consequences of alterations of 3D genome organization. In this review, we summarize the current knowledge on how 3D genome architecture is dysregulated in cancer, with a focus on enhancer highjacking events and their contribution to tumorigenesis. Studying the functional effects of genome architecture perturbations on gene expression in cancer offers a unique opportunity for a deeper understanding of tumor biology and sets the basis for the discovery of novel therapeutic targets

Detection of ground movements in Montjuïc (Barcelona) using TerraSAR-X data

In this study, 28 StripMap TerraSAR-X images were processed using a Persistent Scatterer Interferometry technique in order to detect and analyze superficial deformation phenomena affecting the hill of Montjuic in Barcelona between December 2007 and November 2009. The results show significant displacement values in two main areas affected by different types of superficial displacements, specifically compaction in a former quarry refill and sliding processes. Displacement values of up to 12 mm/ year along the line of sight of the satellite were detected in the area near the Perez de Rozas baseball stadium whereas values of up to 7 mm/year were found in the vicinity of Costa i Llobera gardens. For each deformation area, high resolution deformation velocity data were analyzed and integrated with historical images and field data to interpret the detected phenomena

Nucleotide-resolution DNA double-strand breaks mapping by next-generation sequencing

We present a genome-wide method to map DNA double-strand breaks (DSBs) at nucleotide resolution by direct in situ breaks labeling, enrichment on streptavidin, and next-generation sequencing (BLESS). We comprehensively validated and tested BLESS using different human and mouse cells, DSBs-inducing agents, and sequencing platforms. BLESS was able to detect telomere ends, Sce endonuclease-induced DSBs, and complex genome-wide DSBs landscapes. As a proof of principle, we characterized the genomic landscape of sensitivity to replication stress in human cells, and identified over two thousand non-uniformly distributed aphidicolin-sensitive regions (ASRs) overrepresented in genes and enriched in satellite repeats. ASRs were also enriched in regions rearranged in human cancers, with many cancer-associated genes exhibiting high sensitivity to replication stress. Our method is suitable for genome-wide mapping of DSBs in various cells and experimental conditions with a specificity and resolution unachievable by current techniques

The evolution of Wide-Area DInSAR: from regional and national services to the European Ground Motion Service

This study is focused on wide-area deformation monitoring initiatives based on the differential interferometric SAR technique (DInSAR). In particular, it addresses the use of advanced DInSAR (A-DInSAR) techniques, which are based on large sets of synthetic aperture radar (SAR) and Copernicus Sentinel-1 images. Such techniques have undergone a dramatic development in the last twenty years: they are now capable to process big sets of SAR images and can be exploited to realize a wide-area A-DInSAR monitoring. The study describes several initiatives to establish wide-area ground motion services (GMS), both at county- and region-level. In the second part of the study, some of the key technical aspects related to wide-area A-DInSAR monitoring are discussed. Finally, the last part of the study is devoted to the European ground motion service (EGMS), which is part of the Copernicus land monitoring service. It represents the most important wide-area A-DInSAR deformation monitoring system ever developed. The study describes its main characteristics and its main products. The end of the production of the first EGMS baseline product is foreseen for the last quarter of 202

Colibactin DNA-damage signature indicates mutational impact in colorectal cancer

The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin(1) associated with certain strains of Escherichia coli(2), creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics. A survey of somatic mutations at colibactin target sites of several thousand cancer genomes revealed notable enrichment of this motif in colorectal cancers. Moreover, the exact double-strand-break loci corresponded with mutational hot spots in cancer genomes, reminiscent of a trinucleotide signature previously identified in healthy colorectal epithelial cells(3). The present study provides evidence for the etiological role of colibactin in human cancer. Identification of a DNA-damage signature induced by colibactin, a toxin expressed by some strains of Escherichia coli, is enriched in human colorectal cancers.Peer reviewe

BLISS is a versatile and quantitative method for genome-wide profiling of DNA double-strand breaks

Precisely measuring the location and frequency of DNA double-strand breaks (DSBs) along the genome is instrumental to understanding genomic fragility, but current methods are limited in versatility, sensitivity or practicality. Here we present Breaks Labeling In Situ and Sequencing (BLISS), featuring the following: (1) direct labelling of DSBs in fixed cells or tissue sections on a solid surface; (2) low-input requirement by linear amplification of tagged DSBs by in vitro transcription; (3) quantification of DSBs through unique molecular identifiers; and (4) easy scalability and multiplexing. We apply BLISS to profile endogenous and exogenous DSBs in low-input samples of cancer cells, embryonic stem cells and liver tissue. We demonstrate the sensitivity of BLISS by assessing the genome-wide off-target activity of two CRISPR-associated RNA-guided endonucleases, Cas9 and Cpf1, observing that Cpf1 has higher specificity than Cas9. Our results establish BLISS as a versatile, sensitive and efficient method for genome-wide DSB mapping in many applications.National Institute of General Medical Sciences (U.S.) (Grant T32GM007753)National Institute of Mental Health (U.S.) (Grant 5DP1-MH100706)National Institute of Mental Health (U.S.) (Grant 1R01-MH110049