Suchergebnisse

Lamins (A/C and B) are major constituents of the nuclear lamina (NL). Structurally conserved lamina-associated domains (LADs) are formed by genomic regions that contact the NL. Lamins are also found in the nucleoplasm, with a yet unknown function. Here we map the genome-wide localization of lamin B1 in an euchromatin-enriched fraction of the mouse genome and follow its dynamics during the epithelial-to-mesenchymal transition (EMT). Lamin B1 associates with actively expressed and open euchromatin regions, forming dynamic euchromatin lamin B1-associated domains (eLADs) of about 0.3 Mb. Hi-C data link eLADs to the 3D organization of the mouse genome during EMT and correlate lamin B1 enrichment at topologically associating domain (TAD) borders with increased border strength. Having reduced levels of lamin B1 alters the EMT transcriptional signature and compromises the acquisition of mesenchymal traits. Thus, during EMT, the process of genome reorganization in mouse involves dynamic changes in eLADs ; This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI15/00396; CPII14/0006), Ministerio de Economía y Competitividad (MINECO) (SAF2013-40922-R1; FPU14/0407; BFU2016-75008-P), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional-FEDER (SAF2016-76461-R), Generalitat de Catalunya (2014 SGR 32), Fundació FERO, Fundació La Marató TV3, and La Caixa Foundation. We also thank the Advanced Light Microscopy Unit at the CRG for their assistance and the Cellex Foundation for providing research facilities and equipment. M.A.M.-R. acknowledges funding from the European Research Council under the 7th Framework Program (FP7/2010-2015, ERC grant agreement 609989), the European Union's Horizon 2020 research and innovation program (agreement 676556), the Spanish Ministry of Economy and Competitiveness (BFU2013-47736-P), and the Centro de Excelencia Severo Ochoa 2013-2017 (SEV-2012-0208) to the CRG

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy. ; This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI12/01250; CP08/00223; PI16/00253; and CB16/12/00449), MINECO (SAF2013-48849-C2-1-R) to SP, BFU2015-68354 to THS, Breast Cancer Research Foundation (BCRF-17-008) to JA, AGL2014-52395-C2-2-R to DA, Worldwide Cancer Research, Red Temática de Investigación Cooperativa en Cáncer (RD012/0036/005), Fundación Científica de la Asociación Española contra el Cáncer, and Fundació La Marató TV3.THS was supported by institutional funding (MINECO) through theCentres of Excellence Severo Ochoa award and the CERCA Pro-gramme of the Catalan Government, and SS-B, by a Fundació LaCaixa fellowship. We thank La Caixa Foundation and Cellex Foun-dation for provide research facilities and equipment. GV has received f unding from the MINECO (a "Juan de la Cierva Incorporation " fellowship; IJCI-2014-20723). SP was a recipient of a Miguel Servet contract (ISCIII/FIS), and AI, JPC-C, LP-G, and GS-B are supported by contracts from Worldwide Cancer Research, Fundació La MaratóTV3, Fundació FERO, and a FI Fellowship from the Generalitat de Catalunya, respectively.