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News Article | May 3, 2017
Site: phys.org

DNA over-replication is a phenomenon that can have devastating consequences for proliferating cells. When parts of the genome are duplicated more than once, cells suffer from 'genomic instability' (alterations to the structure, composition and/or number of chromosomes), and this process gives rise to aberrant cells as those detected in many carcinomas. The cooperation of two proteins called CDC6 and CDT1 is essential for normal DNA replication but when they are not properly regulated, the genetic material replicates in excess. A paper published in Cell Reports by the DNA Replication Group of the Spanish National Cancer Research Centre (CNIO) sets out the fatal consequences of in vivo re-replication for the first time in mammalian organisms. Genome stability depends, to a great extent, on the accuracy of the DNA replication process. Exposure to UV light or to certain toxic chemicals increase the frequency of errors in the copy that may cause the death or the malignant transformation of the cell. Recent epidemiological studies indicate, for example, that two-thirds of cancerous mutations occur due to replication errors. "Broadly, there are three things that can go wrong in genome replication," explains Juan Méndez, head of the DNA Replication Group at the CNIO and leader of the study. "There may be too many mutations, the cell may replicate prematurely, without being prepared to do so and, finally, it may replicate too far." There are control mechanisms throughout all the key points of the process to prevent these situations. Two of these crucial links are the CDC6 and CDT1 proteins, which assemble the replicating machinery responsible for copying the 2 metres of DNA contained in each cell. Once the process is over, these proteins are inhibited biochemically because if they stay active, they can restart the replication process. In unicellular organisms such as yeast, DNA re-replication can lead to gene amplification, a genetic alteration common in cancer cells. Méndez and his group have used genetically modified mice to demonstrate that when CDC6 and CDT1 accumulate at abnormally high levels, DNA re-replication occurs in some cell types, affecting tissue functionality. Animals that overexpress one or another protein do not present replication issues but those with excessive levels of CDC6 and CDT1 do not survive more than two weeks, affected mainly by the loss of progenitor cells required for the regeneration of gastrointestinal tissue. "Previous cellular studies pointed in the direction that CDT1 deregulation was sufficient to induce over-replication," explains Méndez. However, "in the in vivo studies, we have found that most tissues need the combination of both proteins." What are the implications of this finding? "Cancer cells frequently have a very high basal level of CDC6", says Méndez-, which is related to their high rate of proliferation." Therefore, in these cells, it would be relatively easy to induce re-replication by simply increasing CDT1 levels, which would not affect normal cells. That is, precisely, what Méndez and his group are working on now. Using drugs to increase the levels of this protein, they are trying to determine whether, in the light of the results obtained so far, lethal DNA re-replication can be induced selectively in cancer cells in order to eliminate them from the body. Explore further: DNA replication protein Cdt1 also has a role in mitosis, cancer


News Article | April 18, 2017
Site: www.eurekalert.org

Cross-talk between malignant hepatocytes and neighboring progenitor cells signals progenitor cells to become activated, to expand and to maintain them in an undifferentiated state; thus, progenitor cells become oncogenic and contribute to tumourigenesis The malignant transformation of hepatocytes is the origin of most hepatocellular carcinomas, an aggressive type of liver cancer with high mortality rates. But these cells do not act alone. Research conducted by scientists at the Spanish National Cancer Research Centre (CNIO) reveals how hepatocytes "recruit" and "instruct" liver progenitor cells to contribute to the hepatic lesions. "The cellular origin of liver cancer, as well as the origin of tumour heterogeneity, are not clear yet and may be context-dependent," say the authors in the journal Cell Reports. Hepatocytes -the main liver cells- have been considered the main source of hepatocellular carcinomas but the results of this research provide various novel perspectives. "What we are showing here is that hepatic progenitor cells expand during tumorigenesis and, at one point, they become transformed because of oncogenic hepatocyte cross-talk; this makes them participate in liver tumour development in general, and in hepatocellular carcinomas in particular," explains Nabil Djouder, head of the Growth Factors, Nutrients and Cancer Group at the CNIO and main author of the paper. Thanks to an animal model -generated by Djouder and his team- that fairly reproduces the tumour formation process seen in human hepatocarcinogenesis, and to other genetic experiments, the authors have tried to follow the formation of the lesions and to define the histopathology of the various tumours that develop in this organ, whether benign (regenerative nodules, adenomas) or malignant (hepatocellular carcinoma or HCC). "This is what we've seen: oncogenic hepatocytes lead to hepatocellular carcinoma but, in a model that mimics human hepatocarcinogenesis, progenitor cells also participate in liver tumour heterogeneity. They mostly lead to benign tumours but sometimes they can lead to aggressive carcinomas", points out Djouder. In other words, progenitor cells become oncogenic even though they were not initially transformed. Malignant hepatocytes crosstalk and instruct neighbouring progenitor cells to become activated, maintaining them in an undifferentiated state while at the same time proliferating, becoming oncogenic themselves, and contributing to the lesions. This activation occurs, as shown by this study, when the hepatocytes secrete two substances (?-ketoglutarate and galectin-3) that act and transform progenitor cells. "Blocking galectin-3 can block the cross-talk between these cells thereby reducing tumourigenesis", a finding that could have therapeutic implications, explains Djouder.


News Article | May 3, 2017
Site: www.eurekalert.org

Simultaneous over-expression of two proteins provokes DNA re-replication in some cell types. This phenomenon can lead to cell malignancy but also might be used to attack cancer cells DNA over-replication is a phenomenon that can have devastating consequences for proliferating cells. When parts of the genome are duplicated more than once, cells suffer from 'genomic instability' (alterations to the structure, composition and/or number of chromosomes), and this process gives rise to aberrant cells as those detected in many carcinomas. The cooperation of two proteins called CDC6 and CDT1 is essential for normal DNA replication but when they are not properly regulated, the genetic material replicates in excess. A paper published in Cell Reports by the DNA Replication Group of the Spanish National Cancer Research Centre (CNIO) sets out the fatal consequences of in vivo re-replication for the first time in mammalian organisms. Genome stability depends, to a great extent, on the accuracy of the DNA replication process. Exposure to UV light or to certain toxic chemicals increase the frequency of errors in the copy that may cause the death or the malignant transformation of the cell. Recent epidemiological studies indicate, for example, that two-thirds of cancerous mutations occur due to replication errors. "Broadly, there are three things that can go wrong in genome replication," explains Juan Méndez, head of the DNA Replication Group at the CNIO and leader of the study. "There may be too many mutations, the cell may replicate prematurely, without being prepared to do so and, finally, it may replicate too far." There are control mechanisms throughout all the key points of the process to prevent these situations. Two of these crucial links are the CDC6 and CDT1 proteins, which assemble the replicating machinery responsible for copying the 2 metres of DNA contained in each cell. Once the process is over, these proteins are inhibited biochemically because if they stay active, they can restart the replication process. In unicellular organisms such as yeast, DNA re-replication can lead to gene amplification, a genetic alteration common in cancer cells. Méndez and his group have used genetically modified mice to demonstrate that when CDC6 and CDT1 accumulate at abnormally high levels, DNA re-replication occurs in some cell types, affecting tissue functionality. Animals that overexpress one or another protein do not present replication issues but those with excessive levels of CDC6 and CDT1 do not survive more than two weeks, affected mainly by the loss of progenitor cells required for the regeneration of gastrointestinal tissue. "Previous cellular studies pointed in the direction that CDT1 deregulation was sufficient to induce over-replication," explains Méndez. However, "in the in vivo studies, we have found that most tissues need the combination of both proteins." What are the implications of this finding? "Cancer cells frequently have a very high basal level of CDC6", says Méndez-, which is related to their high rate of proliferation." Therefore, in these cells, it would be relatively easy to induce re-replication by simply increasing CDT1 levels, which would not affect normal cells. That is, precisely, what Méndez and his group are working on now. Using drugs to increase the levels of this protein, they are trying to determine whether, in the light of the results obtained so far, lethal DNA re-replication can be induced selectively in cancer cells in order to eliminate them from the body.


News Article | May 4, 2017
Site: www.biosciencetechnology.com

DNA over-replication is a phenomenon that can have devastating consequences for proliferating cells. When parts of the genome are duplicated more than once, cells suffer from 'genomic instability' (alterations to the structure, composition and/or number of chromosomes), and this process gives rise to aberrant cells as those detected in many carcinomas. The cooperation of two proteins called CDC6 and CDT1 is essential for normal DNA replication but when they are not properly regulated, the genetic material replicates in excess. A paper published in Cell Reports by the DNA Replication Group of the Spanish National Cancer Research Centre (CNIO) sets out the fatal consequences of in vivo re-replication for the first time in mammalian organisms. Genome stability depends, to a great extent, on the accuracy of the DNA replication process. Exposure to UV light or to certain toxic chemicals increase the frequency of errors in the copy that may cause the death or the malignant transformation of the cell. Recent epidemiological studies indicate, for example, that two-thirds of cancerous mutations occur due to replication errors. "Broadly, there are three things that can go wrong in genome replication," explained Juan Méndez, head of the DNA Replication Group at the CNIO and leader of the study. "There may be too many mutations, the cell may replicate prematurely, without being prepared to do so and, finally, it may replicate too far." There are control mechanisms throughout all the key points of the process to prevent these situations. Two of these crucial links are the CDC6 and CDT1 proteins, which assemble the replicating machinery responsible for copying the 2 metres of DNA contained in each cell. Once the process is over, these proteins are inhibited biochemically because if they stay active, they can restart the replication process. In unicellular organisms such as yeast, DNA re-replication can lead to gene amplification, a genetic alteration common in cancer cells. Méndez and his group have used genetically modified mice to demonstrate that when CDC6 and CDT1 accumulate at abnormally high levels, DNA re-replication occurs in some cell types, affecting tissue functionality. Animals that overexpress one or another protein do not present replication issues but those with excessive levels of CDC6 and CDT1 do not survive more than two weeks, affected mainly by the loss of progenitor cells required for the regeneration of gastrointestinal tissue. "Previous cellular studies pointed in the direction that CDT1 deregulation was sufficient to induce over-replication," explained Méndez. However, "in the in vivo studies, we have found that most tissues need the combination of both proteins." What are the implications of this finding? "Cancer cells frequently have a very high basal level of CDC6", said Méndez-, which is related to their high rate of proliferation." Therefore, in these cells, it would be relatively easy to induce re-replication by simply increasing CDT1 levels, which would not affect normal cells. That is, precisely, what Méndez and his group are working on now. Using drugs to increase the levels of this protein, they are trying to determine whether, in the light of the results obtained so far, lethal DNA re-replication can be induced selectively in cancer cells in order to eliminate them from the body.


News Article | December 15, 2016
Site: www.eurekalert.org

Genomic analysis of the Iberian lynx confirms that it is one of the species with the least genetic diversity among individuals, which means that it has little margin for adaptation Spanish scientists have sequenced the genome of the Iberian lynx (Lynx pardinus), currently one of the world's most endangered felines. They have confirmed the "extreme erosion" suffered by its DNA. The Iberian lynx has one of the least genetically-diverse genomes. It is even less diverse than other endangered mammals, such as the cheetah or Tasmanian devil, or birds, like the crested ibis or osprey. The study, being published today in the scientific journal Genome Biology, has been coordinated by scientists from the Doñana Biological Station (CSIC). The Centre for Genomic Regulation (CRG) contributed to this research project from the very beginning including several groups and facilities. In particular, the laboratories of Roderic Guigó, Cedric Notredame, and Toni Gabaldón at the Bioinformatics and Genomics Programme as well as the CRG Bioinformatics unit. This is the first mammal genome of reference generated entirely in Spain. The project, financed by Banco Santander and managed by the Fundación General CSIC, has integrated the efforts of 50 scientists from research groups of 12 institutions, two of them from outside Spain, that cover a broad range of disciplines, including bioinformatics, genomics, oncology, evolution and conservation. The scientists have managed to read and organize 2.4 billion letters of DNA from Candiles, a male lynx born in the Sierra Morena lynx population, who now forms part of a program for breeding in captivity. To do so, they have used new sequencing techniques and developed innovative procedures to generate a high-quality draft genome on a limited budget. A total of 21,257 genes were identified, a number similar to that of human beings and other mammals, and they have been compared to those of cats, tigers, cheetahs and dogs. Specifically, Toni Gabaldón's group at the Centre for Genomic Regulation in Barcelona has compared the Iberian lynx genome with those of other species, attempting to identify genes that have lost their function because they have remained isolated and the existence of a small population of specimens of this species. Researchers have found evidence of modifications in genes related with the senses of hearing, sight and smell to facilitate the adaptation of the lynx to its environment, which have enabled them to become exceptional hunters specialized in rabbits as prey. History and diversity of the Iberian lynx With the aim of studying the history and genetic diversity of the species, analysis was conducted on the genomes of another ten Iberian lynxes from Doñana and Sierra Morena, the only two surviving populations on the Iberian Peninsula, which have been isolated from each other for decades. Researchers have also completed a comparative analysis with a European lynx, to discover the bonds between the two lynxes that inhabit Eurasia. The Iberian lynx began to diverge from its sister species, the Eurasian lynx (Lynx lynx) some 300,000 years ago, and the two species became completely separated some 2,500 years ago. Throughout that period, they continued to cross-breed and exchange genes, probably in the periods between glaciations, when the climatology allowed the species to spread and encounter each other on the Iberian Peninsula and in southern Europe. The demographic history of the Iberian lynx has been marked by three historic declines, the last of which took place some 300 years ago, decimating its population. In addition to this, there was a drastic drop in the number of specimens in the 20th century due to its persecution, the destruction of its habitat, and two major viral epidemics suffered by the rabbit, its main food source. Scientists have interpreted these demographic drops as the cause of the low levels of diversity observed, and warn that this could impair the lynx's capacity to adapt to changes in its environment (climate, disease, etc.). Furthermore, existence of multiple potentially harmful genetic variants has been confirmed, which could be contributing to the reduced survival and reproduction rates of the species. This genetic deterioration is especially marked in the Doñana population-smaller, and isolated for a longer period-which has half the genetic diversity of the Sierra Morena group. Nevertheless, the study reflects the situation before the exchange between the two relict populations and their inter-breeding in captivity were begun. These measures, taken within the Iberian lynx conservation program, have led to improvement of the species' genetic situation in recent years. The use of new genomic resources, within the framework of the project, will contribute to optimizing management aimed at preserving the greatest genetic diversity, in addition to diminishing these populations' genetic defects as much as possible. In addition to Doñana Biological Station (EBD-CSIC), also taking part in the project were the National Center for Genomic Analysis (CNAG-CRG); the Centre for Genomic Regulation (CRG); the Spanish National Cancer Research Center (CNIO); the Evolutionary Genomics Group of the Hospital del Mar Medical Research Institute (IMIM); the Institute of Evolutionary Biology (IBE, CSIC-UPF); the University Institute of Oncology of Asturias (IUOPA); the Institut de Biotecnologia i de Biomedicina and the Unit of Cell Culture of the Autonomous University of Barcelona (UAB); the Biological Research Center (CIB-CSIC) and the Catalan Institution for Research and Advanced Studies (ICREA). Furthermore, the project has received the cooperation of a team from College of Veterinary Medicine of Texas A&M University and the Bioinformatics Research Center of the University of Aarhus (Denmark).


In contrast to the cells in the rest of the body, sex cells hold half the number of chromosomes (they are haploid) as a result of this special kind of cell division. In meiosis, a precursor cell —primordial germ cell— produces four spermatozoids during spermatogenesis, while only one oocyte is formed during oogenesis (the other three cells die during the process). Mice deficient in RingoA, generated in Nebreda's Signalling and Cell Cycling Laboratory, are apparently healthy but both sexes are completely sterile. After three years of experiments, IRB Barcelona postdoctoral researchers Petra Mikolcevic and Michitaka Isoda describe the molecular imbalances that occur during meiosis as a result of the absence of this protein. This study sheds new light on a key process for all forms of life that engage in sexual reproduction. "We all start life through meiosis so understanding how this process works is intellectually interesting," says Nebreda. Although meiosis was first described in the late 19th century, "many questions remain unanswered," explains this scientist, holder of a European Research Council grant. "There are no good in vitro models available to study meiosis. It is difficult to extract spermatocytes and to perform studies in plates; they have to be studied in the testicles. And oocytes are even worse because ovules are formed in early stages of development and working with embryos is technically complex." The scientists have discovered that RingoA is a key activator of Cdk2, the protein kinase with which it forms a complex required for meiosis. In fact, the genetic mouse model deficient in Cdk2, which was reported 12 years ago by Mariano Barbacid's group at CNIO, is also viable but sterile and shows the exact same alterations in meiosis as those observed by the researchers at IRB Barcelona. "In biology, if two practically indistinguishable phenotypes are obtained, it is an indication that the proteins have the same function and that they may work together." What was not known until now was that RingoA is the key partner for Cdk2 in meiosis, as Cdk2 normally forms complexes with another family of proteins called cyclins. The study demonstrates that RingoA is active at telomeres—structures that protect the ends of chromosomes and where Cdk2 is also found.  During meiosis, telomeres allow chromosomes to attach to the nuclear membrane, thus allowing them to exchange DNA fragments. This recombination of chromosomes is an essential feature of meiosis. Without the RingoA-Cdk2 complex, the telomeres of the chromosomes do not tether to the membrane but rather float in the nucleus, leading to chaotic recombination. The breaks in DNA needed for fragment exchange are not repaired and thus meiosis is not completed. Consequently, sex cells are not formed. "It would not be unreasonable to consider the development of a male contraceptive based on RingoA-Cdk2 inhibitors," proposes Nebreda. In the same way that women produce oocytes during embryo development, men can produce spermatozoids throughout adulthood. "If the pharmaceutical industry wanted to invest in this field, we have the biochemical techniques set up for the identification of inhibitors." Explore further: Researchers identify first sex chromosome gene involved in meiosis and male infertility More information: Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope. Nature Comms. (2016, 30 March): DOI: 10.1038/NCOMMS11084


News Article | February 6, 2017
Site: www.medicalnewstoday.com

During the 'in vivo' reprogramming process, cellular telomeres are extended due to an increase in endogenous telomerase. This is the main conclusion of a paper published in Stem Cell Reports by a team from the Spanish National Cancer Research Centre (CNIO). Their observations show, for the first time, that the reprogramming of living tissue results in telomerase activation and telomere elongation; thus reversing one of the hallmarks of aging: 'the presence of short telomeres'. "We have found that when you induce cell dedifferentiation in an adult organism, the telomeres become longer, which is consistent with cellular rejuvenation", explains María A. Blasco, head of the CNIO Telomeres and Telomerase Group and leader of this research. This lengthening of the telomeres is an unequivocal sign of cell rejuvenation, which has been quantified for the first time here in a living organism. Blasco and her colleagues have worked with the so-called "reprogrammable mice" - created by Manuel Serrano, also a CNIO researcher, whose group is also involved in this project. Broadly speaking, the cells of these transgenic animals carry the four Yamanaka factors (OSKM) whose expression is turned on when an antibiotic is administered. In doing so, the cells regress to an embryonic-like state, a condition known as known as pluripotency. In light of the importance of telomeres in tissue regeneration, ageing and cancer, the authors decided to analyse the changes that occur in these protective structures of the chromosomes during the 'in vivo' reprogramming process, which leads to dedifferentiation of the tissues. Their observations indicate that this process entails a lengthening of the telomeres, a marker of cellular rejuvenation. This elongation occurs, according to this research, due to the action of telomerase. "What we have seen for the first time is the induction of telomerase 'in vivo'," explained Blasco and Rosa M. Marion, the leading authors of the paper. "To date, we do not know of any study that describes the induction of endogenous telomerase by defined transcription factors in the context of adult tissues," say the authors. The loss of cell differentiation is a phenomenon that takes place in a physiological context. It occurs during tissue regeneration and also in tumourigenesis. In fact, "this is increasingly considered one of the critical initial steps in cancer development," as stated in the paper. Dedifferentiation induced by 'in vivo' reprogramming, as well as the dedifferentiation associated with the initiation of cancer, involve "similar changes in the telomeres", say the authors. In both of these processes, we see the activation of telomerase and the subsequent elongation of the telomeres. A better knowledge of the changes described in the telomeres during 'in vivo' reprogramming and in pathological processes, such as cancer, will improve our understanding about the molecular events associated with cellular differentiation and, most likely, with other processes that involve cell plasticity. This work has been funded funded by the Spanish Ministry of Economy and Competiveness (PLAN RETOS) and by the Fundación Botín. Article: Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis, Rosa M. Marión, Isabel López de Silanes, Lluc Mosteiro, Benjamin Gamache, Maria Abad, Carmen Guerra, Diego Megías, Manuel Serrano and Maria A. Blasco, Stem Cell Reports, doi: 10.1016/j.stemcr.2017.01.001, published online 2 February 2017.


SUMO protein with the areas marked with ubiquitin in green. Credit: CNIO Three years ago, the research team directed by Óscar Fernández-Capetillo, head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), obtained, for the first time, a panoramic view of the proteins that intervene in one of the most important and delicate cellular processes: the copying of genetic material during cellular division. They observed that the parts of the genome where the DNA was copied were also very rich in the modification by some very particular proteins, SUMOylations, and poor in others, ubiquitinations, but they were unable to understand why. The continuation of the paper, published today in the Nature Structural & Molecular Biology journal, reveals how the balance between these chemical markers in these regions is, in fact, key for the division of genetic material. During this process, the USP7 protein travels with an entourage of molecules that form part of the replisome—a set of proteins involved in copying the DNA—and eliminates the ubiquitination marks of proteins in the complex, thus explaining the low concentration of ubiquitin in these areas. "USP7 acts as an traffic officer that regulates the marks or traffic signs near the replisome. Eliminating ubiquitin prevents the proteins at the replisome from being expelled, thus favouring their concentration and the DNA copying process," explains Fernández-Capetillo. As the team described in the previous paper, replisomes contain up to 50 different proteins that participate in the delicate process of copying genetic material. Some proteins open DNA's double helix, others twist it to favour copying, others stabilise it, etc. They all move together through the genome to ensure a complete copy. In order to understand the role of USP7 and its cutting action on ubiquitin marks during the DNA copying process, the researchers used advanced protein tools. "We knew that replisome proteins could present both modifications simultaneously [ubiquitinations and SUMOylations], but we did not know how they worked," explains Fernández-Capetillo. "We now know that USP7 eliminates the ubiquitin marks on proteins that are also SUMOylated in replication areas, which explains why there is a low concentration of ubiquitin and high levels of SUMO." This balance between SUMO and ubiquitin establishes a code that regulates the concentration of proteins in the replisome. "If a protein is SUMOylated, it becomes enriched in the replisome, but if it is also ubiquitinated, it is expelled. This is a code of signals or flags that regulates the concentration of factors in the DNA replication area," say the researchers. Apart from being of academic interest, these studies are relevant for chemotherapy. USP7 inhibitors are currently being studied as possible anti-cancer agents in pre-clinical tests. "The model that had been proposed is that the compounds increase p53 levels, resulting in the suicide of tumour cells. Our data indicate that USP7 is essential for genome replication in cells with or without p53." With these data, the authors of the paper warn that these molecules may not be specifically anti-tumour agents. "We believe they inhibit the cell division process regardless of whether the cells are cancerous or healthy and, therefore, their use for treating cancer in the future will have to be reconsidered." Explore further: Researchers 'capture' the replication of the human genome for the first time More information: Emilio Lecona et al. USP7 is a SUMO deubiquitinase essential for DNA replication, Nature Structural & Molecular Biology (2016). DOI: 10.1038/nsmb.3185


Millions of human cells are constantly dividing to repair tissue damage and ensure continuity. This is one of the most complex cellular processes, and in order for it to be successful, cells must produce a copy of their genetic material (DNA). Researchers from the Spanish National Cancer Research Centre (CNIO) have discovered the critical role of the POLD3 protein in this DNA replication process; without POLD3, cells do not divide, and even the embryonic development process may be curtailed.


News Article | November 17, 2016
Site: www.eurekalert.org

The Structural Biology and Biocomputing Programme, together with the National Institute Bioinformatics unit at the Spanish National Cancer Research Centre, has participated coordinating the data analysis and making data accessible in the BLUEPRINT project The International Human Epigenome Consortium (IHEC) publishes simultaneously a collection of 41 papers that contain major advances in the study of the Human epigenome - 24 of which appear today in Cell Press magazines. The Structural Biology and Biocomputing Programme together with the National Institute Bioinformatics unit at the National Cancer Research Center (CNIO) participate signing different studies and leading three of them. One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single cell and from one DNA sequence, or genome. We have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. The identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome - the epigenome - which acts as a blueprint unique to each cell type and developmental stage. Unlike the genome, the epigenome changes as cells develop and in response to changes in the environment. Defects in the factors that read, write and erase the epigenetic blueprint are involved in many diseases. The comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes. A collection of 41 coordinated papers now published by scientists from across the International Human Epigenome Consortium (IHEC) sheds light on these processes, taking global research in the field of epigenomics a major step forward. A set of 24 manuscripts has been released as a package in Cell and Cell Press-associated journals, and an additional 17 papers have been published in other high-impact journals. The Structural Biology and Biocomputing Programme, together with the National Institute Bioinformatics unit at the CNIO, headed by Alfonso Valencia, has participated coordinating the data analysis and making data accessible in the BLUEPRINT project, the major European partner framed in IHEC with 42 partner organisations, representing 33 academic groups and 9 companies (mostly Small and Medium Enterprises (SMEs)) from 12 European countries. "Our work has been making the data accessible to the other research groups," explains Valencia. "The project has generated a large volume of epigenomic data and it was necessary to develop the methods and systems to analyze them." And that is what they have done, with the aim of "facilitating the analysis of biological information". The major contribution has been the BLUEPTRINT Data Analysis Portal an interface that facilitates interactive exploration of genomic regions, genes, and pathways in the context of differentiation of hematopoietic lineages (visit at: http://blueprint-data. ) In addition to this role of data management, Valencia's group has led several works in which they have developed their own systems of analysis. For example, the use of assortativity for the analysis of the 3D configuration of the genome, published in Genome Biology. "It has been a very positive experience because it has provided us with tools that have served to analyze the data of this project and that in the future will serve for the analysis of the data that are generated in epigenomics," says Valencia. "BLUEPRINT has produced more new science and more understanding of blood cell disease than we could have imagined at the outset," "We have made the data of >1000 datasets publicly available" says Henk Stunnenberg from Radboud University, The Netherlands, former Chair of the IHEC International Scientific Steering Committee and coordinator of the EU-funded BLUEPRINT project. "Moreover, we have forged an alliance of researchers and innovative companies from around Europe and, working closely with international partners, we already see results that, in time, will improve the lives of patients." These papers represent the most recent work of IHEC member projects from Canada, the European Union, Germany, Japan, Singapore, and the United States. The collection of publications showcases the achievements and scientific progress made by IHEC in core areas of current epigenetic investigations.

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