Suchergebnisse

Nuclear architecture is decisive for the assembly of transcriptional responses. However, how chromosome organization is dynamically modulated to permit rapid and transient transcriptional changes in response to environmental challenges remains unclear. Here we show that hyperosmotic stress disrupts different levels of chromosome organization, ranging from A/B compartment changes to reduction in the number and insulation of topologically associating domains (TADs). Concomitantly, transcription is greatly affected, TAD borders weaken, and RNA Polymerase II runs off from hundreds of transcription end sites. Stress alters the binding profiles of architectural proteins, which explains the disappearance of local chromatin organization. These processes are dynamic, and cells rapidly reconstitute their default chromatin conformation after stress removal, uncovering an intrinsic organization. Transcription is not required for local chromatin reorganization, while compartment recovery is partially transcription-dependent. Thus, nuclear organization in mammalian cells can be rapidly modulated by environmental changes in a reversible manner. ; The study was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-64437-P and FEDER, BFU2014-52125-REDT, and BFU2014-51672-REDC to F.P.; BFU2017-85152-P and FEDER to E.d.N.), the Catalan Government (2017 SGR 799), the Fundación Botín, and the Banco Santander through its Santander Universities Global Division to F.P. and the Unidad de Excelencia Maria de Maeztu, MDM-2014-0370. F.P. is recipient of an ICREA Acadèmia (Generalitat de Catalunya). M.B. received the support of the European Research Council (ERC Synergy Grant 4D Genome 609989) and CERCA.

Although single base-pair resolution DNA methylation landscapes for embryonic and different somatic cell types provided important insights into epigenetic dynamics and cell-type specificity, such comprehensive profiling is incomplete across human cancer types. This prompted us to perform genome-wide DNA methylation profiling of 22 samples derived from normal tissues and associated neoplasms, including primary tumors and cancer cell lines. Unlike their invariant normal counterparts, cancer samples exhibited highly variable CpG methylation levels in a large proportion of the genome, involving progressive changes during tumor evolution. The whole-genome sequencing results from selected samples were replicated in a large cohort of 1112 primary tumors of various cancer types using genome-scale DNA methylation analysis. Specifically, we determined DNA hypermethylation of promoters and enhancers regulating tumor-suppressor genes, with potential cancer-driving effects. DNA hypermethylation events showed evidence of positive selection, mutual exclusivity and tissue specificity, suggesting their active participation in neoplastic transformation. Our data highlight the extensive changes in DNA methylation that occur in cancer onset, progression and dissemination. ; This work was supported by Institute of Health Carlos III ISCIII Project no. PI11/00321, Spanish Cancer Research Network (RTICC) no. RD12/0036/0039; European Development Regional Fund, 'A way to achieve Europe' ERDF (SAF2014-55000-R), Sandra Ibarra Foundation; Olga Torres Foundation; Cellex Foundation; AGAUR 2014SGR633 grant; Health and Science Departments of the Catalan government (Generalitat de Catalunya) and European Community's Seventh Framework Program (FP7/2007-2013), grant HEALTH-F5-2011-282510 – BLUEPRINT. HH is a Miguel Servet (CP14/00229) ISCII researcher.

How repetitive elements, epigenetic modifications, and architectural proteins interact ensuring proper genome expression remains poorly understood. Here, we report regulatory mechanisms unveiling a central role of Alu elements (AEs) and RNA polymerase III transcription factor C (TFIIIC) in structurally and functionally modulating the genome via chromatin looping and histone acetylation. Upon serum deprivation, a subset of AEs pre-marked by the activity-dependent neuroprotector homeobox Protein (ADNP) and located near cell-cycle genes recruits TFIIIC, which alters their chromatin accessibility by direct acetylation of histone H3 lysine-18 (H3K18). This facilitates the contacts of AEs with distant CTCF sites near promoter of other cell-cycle genes, which also become hyperacetylated at H3K18. These changes ensure basal transcription of cell-cycle genes and are critical for their re-activation upon serum re-exposure. Our study reveals how direct manipulation of the epigenetic state of AEs by a general transcription factor regulates 3D genome folding and expression. ; This work was supported by the Spanish Ministry of Economy and Competitiveness Centro de Excelencia Severo Ochoa 2013–2017 SEV-2012-0208 (to CRG) and BFU2016-76141-P (to S.d.l.L.); ACER (to CRG); Italian Association for Cancer Research (AIRC, grant IG16877 to G.D.); the Cancer Research UK Programme Foundation (CR-UK C47547/A21536 to A.V.); a Wellcome Trust Investigator Award (200818/Z/16/Z to A.V.); and the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007–2013/ERC Synergy grant agreement 609989-4DGenome to M.B.). We acknowledge the support of the Spanish Ministry of Science, Innovation, and Universities to the EMBL partnership, the CERCA Programme/Generalitat de Catalunya , and the Centro de Excelencia Severo Ochoa. The ERC provided funding for the open access charge. The proteomics analyses were performed at the CRG/UPF Proteomics Unit (part of the of Proteored, PRB3; supported by grant PT17/0019 [ISCIII and ERDF]). This work was also supported by the Ligue Contre le Cancer (to M.T.)