Suchergebnisse

Chromosome conformation capture techniques, such as Hi-C, are fundamental in characterizing genome organization. These methods have revealed several genomic features, such as chromatin loops, whose disruption can have dramatic effects in gene regulation. Unfortunately, their detection is difficult; current methods require that the users choose the resolution of interaction maps based on dataset quality and sequencing depth. Here, we introduce Binless, a resolution-agnostic method that adapts to the quality and quantity of available data, to detect both interactions and differences. Binless relies on an alternate representation of Hi-C data, which leads to a more detailed classification of paired-end reads. Using a large-scale benchmark, we demonstrate that Binless is able to call interactions with higher reproducibility than other existing methods. Binless, which is freely available, can thus reliably be used to identify chromatin loops as well as for differential analysis of chromatin interaction maps. ; This work has been partially supported by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Synergy grant agreement 609989 (4Dgenome), the European Union's Horizon 2020 research and innovation programme (agreement 676556) as well as the Spanish MINECO (BFU2017-85926-P). We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme / Generalitat de Catalunya. We also acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement and the Co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program

To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation. ; Work at the M.A.M.-R. lab was supported by the European Research Council under the 7th Framework Program FP7/2007-2013 (ERC grant agreement 609989), the European Union's Horizon 2020 research and innovation programme (grant agreement 676556), the Ministry of Economy and Competitiveness (BFU2017-85926-P), and the Agència de Gestió d'Ajuts Universitaris i de Recerca, AGAUR (SGR468). Work at CRG, BIST, and UPF was in part funded by the Spanish Ministry of Economy and Competitiveness, ''Centro de Excelencia Severo Ochoa 2013-2017'' (SEV-2012-0208), and ''Centro de Excelencia María de Maeztu 2016-2019.'' This article/publication is based upon work from COST Action CA18127, supported by COST (European Cooperation in Science and Technology)

Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Chromosome conformation capture (3C)-based experiments combined with computational modelling are pivotal for unveiling 3D chromosome structure. Here, we introduce TADdyn, a tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci in a completely data-driven way. We apply TADdyn on in situ Hi-C time-course experiments studying the reprogramming of murine B cells to pluripotent cells, and characterize the structural rearrangements that take place upon changes in the transcriptional state of 21 genomic loci of diverse expression dynamics. By measuring various structural and dynamical properties, we find that during gene activation, the transcription starting site contacts with open and active regions in 3D chromatin domains. We propose that these 3D hubs of open and active chromatin may constitute a general feature to trigger and maintain gene transcription. ; This work was partially supported by the European Research Council under the 7th Framework Program FP7/2007-2013 (ERC grant agreement 609989 to M.A.M-R. and T.G.), the European Union's Horizon 2020 research and innovation programme (grant agreement 676556 to M.A.M-R.) and the Spanish Ministerio de Ciencia e Innovación (BFU2013-47736-P and BFU2017-85926-P to M.A.M-R. as well as IJCI-2015-23352 to I.F.). R.S. is supported by the Netherlands Organization for Scientific Research (VENI 91617114) and an Erasmus MC Fellowship. We also knowledge support from "Centro de Excelencia Severo Ochoa 2013-2017", SEV-2012-0208 the Spanish ministry of Science and Innovation to the EMBL partnership and the CERCA Programme/Generalitat de Catalunya to the CRG. We also acknowledge support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement and the Co-financing by the Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program to CNAG