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Hematopoiesis is one of the best characterized biological systems but the connection between chromatin changes and lineage differentiation is not yet well understood. We have developed a bioinformatic workflow to generate a chromatin space that allows to classify 42 human healthy blood epigenomes from the BLUEPRINT, NIH ROADMAP and ENCODE consortia by their cell type. This approach let us to distinguish different cells types based on their epigenomic profiles, thus recapitulating important aspects of human hematopoiesis. The analysis of the orthogonal dimension of the chromatin space identify 32,662 chromatin determinant regions (CDRs), genomic regions with different epigenetic characteristics between the cell types. Functional analysis revealed that these regions are linked with cell identities. The inclusion of leukemia epigenomes in the healthy hematological chromatin sample space gives us insights on the healthy cell types that are more epigenetically similar to the disease samples. Further analysis of tumoral epigenetic alterations in hematopoietic CDRs points to sets of genes that are tightly regulated in leukemic transformations and commonly mutated in other tumors. Our method provides an analytical approach to study the relationship between epigenomic changes and cell lineage differentiation. Method availability: https://github.com/david-juan/ChromDet. ; European Union's Seventh Framework Programme [FP7/2007–2013, 282510 (BLUEPRINT)]; Spanish Ministry of Economy, Industry and Competitiveness and European Regional Development Fund [Project Retos BFU2015–71241-R]. Funding for open access charge: Project Retos BFU2015–71241-R (to A.V.). ; Peer Reviewed ; Postprint (published version)

Hematopoiesis is one of the best characterized biological systems but the connection between chromatin changes and lineage differentiation is not yet well understood. We have developed a bioinformatic workflow to generate a chromatin space that allows to classify 42 human healthy blood epigenomes from the BLUEPRINT, NIH ROADMAP and ENCODE consortia by their cell type. This approach let us to distinguish different cells types based on their epigenomic profiles, thus recapitulating important aspects of human hematopoiesis. The analysis of the orthogonal dimension of the chromatin space identify 32,662 chromatin determinant regions (CDRs), genomic regions with different epigenetic characteristics between the cell types. Functional analysis revealed that these regions are linked with cell identities. The inclusion of leukemia epigenomes in the healthy hematological chromatin sample space gives us insights on the healthy cell types that are more epigenetically similar to the disease samples. Further analysis of tumoral epigenetic alterations in hematopoietic CDRs points to sets of genes that are tightly regulated in leukemic transformations and commonly mutated in other tumors. Our method provides an analytical approach to study the relationship between epigenomic changes and cell lineage differentiation. Method availability: https://github.com/david-juan/ChromDet. ; European Union's Seventh Framework Programme [FP7/2007–2013, 282510 (BLUEPRINT)]; Spanish Ministry of Economy, Industry and Competitiveness and European Regional Development Fund [Project Retos BFU2015–71241-R]. Funding for open access charge: Project Retos BFU2015–71241-R (to A.V.). ; Peer Reviewed ; Postprint (published version)

11 páginas, 7 figuras -- PAGS nros. 2812-2822 ; Genomic DNA is packed in chromatin fibers organized in higher-order structures within the interphase nucleus. One level of organization involves the formation of chromatin loops that may provide a favorable environment to processes such as DNA replication, transcription, and repair. However, little is known about the mechanistic basis of this structuration. Here we demonstrate that cohesin participates in the spatial organization of DNA replication factories in human cells. Cohesin is enriched at replication origins and interacts with prereplication complex proteins. Down-regulation of cohesin slows down S-phase progression by limiting the number of active origins and increasing the length of chromatin loops that correspond with replicon units. These results give a new dimension to the role of cohesin in the architectural organization of interphase chromatin, by showing its participation in DNA replication ; This work was supported by the Spanish Ministry of Science and Innovation (J.M., A.L., and I.C.), Consolider Ingenio 2010 and Fundación Caja Madrid (J.M. and A.L.), Comunidad de Madrid (I.C.), and Institut National du Cancer and Association pour la Recherche sur le Cancer (E.S.). E.G. and V.C. were supported by the Fondation pour la Recherche Médicale and Institut National du Cancer, respectively. A.I. was supported by a fellowship from the Basque Government ; Peer reviewed

This article belongs to the Special Issue Innovative Processing Technologies for Developing Functional Ingredients and Food Products with Health Benefits from Grains. ; Germination is an efficient and natural strategy that allows the modification of the nutritional value and the nutraceutical properties of seeds, enabling one to tailor the process according to its final use. This study aimed at optimization of germination conditions to produce novel lentil flours with improved nutritional and functional features. Response Surface Methodology (RSM) was applied to model the effect of temperature (15–27 °C) and time (1–5 days) on different nutritional and quality parameters of lentil flours including proximate composition, content and profile of fatty acids, content of phytic acid, ascorbic acid and γ-aminobutyric acid (GABA), content and profile of phenolic compounds, antioxidant activity, expected glycemic index (GI) and color during germination. As shown by RSM polynomial models, sprouting promoted the reduction of phytic acid content and enhanced the levels of ascorbic acid, GABA, insoluble phenolic compounds, antioxidant activity and expected GI, and modified the color of the resultant lentil flours. RSM optimization of germination temperature and time using desirability function revealed that the optimal process conditions to maximize the nutritional, bioactive and quality properties of sprouted lentil flours were 21 °C for 3.5 days. ; This research was funded by Agrotechnological Institute (ITACyL) (Castilla y León. Spain) and European Union through FEDER, grant number Invfood 2018-400. ; Peer reviewed

BACKGROUND: Network analysis is a powerful way of modeling chromatin interactions. Assortativity is a network property used in social sciences to identify factors affecting how people establish social ties. We propose a new approach, using chromatin assortativity, to integrate the epigenomic landscape of a specific cell type with its chromatin interaction network and thus investigate which proteins or chromatin marks mediate genomic contacts. RESULTS: We use high-resolution promoter capture Hi-C and Hi-Cap data as well as ChIA-PET data from mouse embryonic stem cells to investigate promoter-centered chromatin interaction networks and calculate the presence of specific epigenomic features in the chromatin fragments constituting the nodes of the network. We estimate the association of these features with the topology of four chromatin interaction networks and identify features localized in connected areas of the network. Polycomb group proteins and associated histone marks are the features with the highest chromatin assortativity in promoter-centered networks. We then ask which features distinguish contacts amongst promoters from contacts between promoters and other genomic elements. We observe higher chromatin assortativity of the actively elongating form of RNA polymerase 2 (RNAPII) compared with inactive forms only in interactions between promoters and other elements. CONCLUSIONS: Contacts among promoters and between promoters and other elements have different characteristic epigenomic features. We identify a possible role for the elongating form of RNAPII in mediating interactions among promoters, enhancers, and transcribed gene bodies. Our approach facilitates the study of multiple genome-wide epigenomic profiles, considering network topology and allowing the comparison of chromatin interaction networks. ; The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282510 (BLUEPRINT) and in the framework of the ...

El pdf del artículo es la versión post-print. ; Macrophages play a relevant role ininnate and adaptive immunity depending on the balance of the stimuli received. From an analytical and functional point of view, macrophage stimulation can be segregated into three main modes, as follows: innate, classic, and alternative pathways. These differential activations result in the expression of specific sets of genes involved in the release of pro-or anti-inflammatory stimuli. In the present work, we have analyzed whether specific metabolic patterns depend on the signaling pathway activated. A[1,2-13C2]glucose tracer-based metabolomics approach has been used to characterize the metabolic flux distributions in macrophages stimulated through the classic, innate, and alternative pathways. Using this methodology combined with mass isotopomer distribution analysis of the new formed metabolites, the data show that activated macrophages are essentially glycolytic cells, and a clear cut off between the classic/innate activation and the alternative pathway exists. Interestingly, macrophage activation through LPS/IFN-γ or TLR-2, -3, -4, and -9 results in similar flux distribution patterns regardless of the pathway activated. However, stimulation through the alternative pathway has minor metabolic effects. Themolecular basis of the differences between these two types of behavior involves a switch in the expression of 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase (PFK2) from the liver type-PFK2 to the more active ubiquitous PFK2 isoenzyme, which responds to Hif-1α activation and increases fructose-2,6-bisphosphate concentration and the glycolytic flux. However, using macrophages targeted for Hif-1α, the switch of PFK2 isoenzymes still occurs in LPS/IFN-γ-activated macrophages, suggesting that this pathway regulates ubiquitous PFK2 expression through Hif-1a-independent mechanisms. Copyright © 2010 by The American Association of Immunologists, Inc. ; This work was supported by European Commission (FP7) Etherpath KBBE-Grant Agreement no. 222639, Grants SAF2005-01627, SAF2008-00164, and BFU2008- 02161 from Ministerio de Ciencia e Innovacio´n of the Spanish Government, 2005SGR00204 from the Generalitat de Catalunya, S-BIO-0283/2006 from Comunidad de Madrid, Red Temática de Investigación Sobre Cáncer (RETICC RD6/0020/ 0046) and Red Temática de Investigación Sobre Enfermedades Cardiovasculares (RECAVA RD6/0014/006), and FIS-RECAVA RD06/0014/0025. RECAVA and Ciberehd are funded by Instituto de Salud Carlos III. J.-C.R.-P. is supported by a fellowship from the University of Barcelona. ; Peer Reviewed

This article belongs to the Special Issue Development of Functional Food Ingredients from Natural Resources. ; The study evaluated the effect of autoclaving as a hydrothermal treatment on the quality and bioactivity of wheat bran (WB) with the objective of producing a natural ingredient with enhanced healthy properties. Nutritional, antioxidant, techno-functional and sensorial parameters were studied, and temperatures of 100, 115 and 130 °C were explored. Of these, 130 °C was found to be the best treatment, resulting in an ingredient with high storage stability, antioxidant properties, a four-fold increase in the concentration of free ferulic acid (compared with non-treated WB), and increased content of apigenin-6-C-arabinoside-8-C-hexoside, a flavonoid with reported antioxidant and antifungal properties. On the other hand, the autoclave treatment enhanced water absorption capacity and reduced WB pasting viscosity, mainly at higher temperature (130 °C), which would allow incorporation of the treated WB in liquid matrices such as juices, soups or milkshakes, among others. Although the glycemic index (GI) of the autoclaved samples increased, the use of intermediate particle size of 106 to 300 µm could contribute to the reduction of the glycemic load. ; This research was funded by European Union through FEADER project Biodough (PEP 2017-807) 2018–2020. FEDER/Ministry of Science, Innovation and Universities-Spanish Agency of Research (AEI/Spain and FEDER/UE), grant number AGL2017-83718R. P.A. Caballero, F. Ronda and A.L. Gutierrez also thank the collaboration grant between ITACYL and University of Valladolid and to MINECO/FEDER (AGL2015-63849-C2-2-R) and the Junta de Castilla y León/FEDER (VA165G18) for their financial support. ; Peer reviewed

Epigenetic communication through histone and cytosine modifications is essential for gene regulation and cell identity. Here, we propose a framework that is based on a chromatin communication model to get insight on the function of epigenetic modifications in ESCs. The epigenetic communication network was inferred from genome-wide location data plus extensive manual annotation. Notably, we found that 5-hydroxymethylcytosine (5hmC) is the most-influential hub of this network, connecting DNA demethylation to nucleosome remodeling complexes and to key transcription factors of pluripotency. Moreover, an evolutionary analysis revealed a central role of 5hmC in the co-evolution of chromatin-related proteins. Further analysis of regions where 5hmC co-localizes with specific interactors shows that each interaction points to chromatin remodeling, stemness, differentiation, or metabolism. Our results highlight the importance of cytosine modifications in the epigenetic communication of ESCs. ; We thank Prof. Stunnenberg and all members of BLUEPRINT Consortium forcritical comments. The research leading to these results has received fundingfrom the European Union's Seventh Framework Programme (FP7/2007-2013)under grant agreement number 282510 (BLUEPRINT) ; Sí

This article belongs to the Special Issue Marine Bioactive Natural Product Studies in Europe. ; Metabolic syndrome (MetS) greatly increases the risk of cardiovascular diseases and type 2 diabetes mellitus. The aim of this study was to evaluate the efficacy of functional snacks containing a combination of wakame (W) and carob pod (CP) flours in reducing markers associated with MetS. The mechanisms of action underlying these effects were also evaluated. In vitro approaches were carried out in mature 3T3-L1 adipocytes and RAW 264.7 macrophages treated with different doses of extracts from W, CP, or a combination of both. Furthermore, an in vivo experiment was conducted in rats with MetS treated with normal-caloric diets containing different snack formulations with combinations of 1/50 (snack A) or 1/5 of wakame/carob (snack B). In vitro experiments results indicated that both W and CP had delipidating effects, but only the latter induced anti-inflammatory and anti-hypertensive effects. As far as the in vivo study is concerned, snack B was ineffective and snack A showed an anti-hypertensive effect in rats with MetS. The present study shows for the first time the in vitro efficacy of a W and CP combination as an anti-inflammatory, delipidating, and anti-hypertensive tool, and its potential usefulness in treating MetS. ; This study has been supported by the National Institute for Agricultural and Food Research and Technology of Spain (INIA: RTA2014-0037-C02), University of the Basque Country (ELDUNANOTEK UFI11/32), Instituto de Salud Carlos III (CIBERobn), and the Basque Government (IT-572-13). ; Peer reviewed

The recent interest in diversification in food consumption and the current salinization and desertification processes of farmland have placed the focus on halophytic plants as new food, making necessary the characterization of their biochemical composition and the identification of possible bioactive compounds. In this work, three edible halophytic plants were characterized: common iceplant (Mesembryanthemum crystallinum), sea fennel (Crithmum maritimum), and seaside arrowgrass (Triglochin maritima). The plants studied were a good source of minerals. Sea fennel showed high contents of dietary fibre and calcium (8.5 ppm, wet weight), common iceplant had a high potassium content (6500 ppm, wet weight), while seaside arrowgrass presented high levels of iron (62 ppm, wet weight). The glucose content of the three species was below 30 mg/g per dried weight. The Sb, Pb, Cr, As, Cd, and Hg content was negligible. Polyunsaturated fatty acids, mainly α-linolenic and linoleic acid, prevailed in the three species analyzed. Hydroxycinnamic and hydroxybenzoic acids predominated in common iceplant and sea fennel. Glycosylated flavones, especially isoorientin, prevailed in seaside arrowgrass. These plants present a relevant nutritional profile for which their use as foods or ingredients should be promoted. ; This work was supported by the Spanish Ministry of Economy and Competitiveness project under Grant (number AGL2014-52825-R) and cofounded with European Union ERDF funds (European Regional Development Fund). Author Sánchez-Faure was also funded by the Spanish Ministry of Economy and Competitiveness (fellowship number BES-2015-074420). ; Peer reviewed

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers. ; Work in MPC lab is supported by Liverpool University, Newcastle University and a Wellcome Institutional Support Fund Award. Work done in A.G.'s lab was supported by Bulgarian National Science Fund grant # DN11/17. Work in the PP lab is supported by grants from the Agence Nationale pour la Recherche (ANR), the Ligue Contre le Cancer (équipe labellisée), SIRIC Montpellier Cancer (INCa Inserm DGOS 12553) and the MSDAvenir fund. ULM was funded by the Royal Society RG170342. IHL was funded from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 754510. Work in the DR lab is supported by a Wellcome Trust Seed Award in Science (206103/Z/17/Z). Work of JMGH was funded by a Wellcome Trust Investigator Award [106951/Z/15/Z] and a Royal Society Wolfson Research Merit Award