Publications by authors named "Biola M Javierre"

20 Publications

  • Page 1 of 1

The Genome in a Three-Dimensional Context: Deciphering the Contribution of Noncoding Mutations at Enhancers to Blood Cancer.

Front Immunol 2020 7;11:592087. Epub 2020 Oct 7.

3D Chromatin Organization Group, Josep Carreras Leukaemia Research Institute (IJC), Germans Trias i Pujol, Badalona, Spain.

Associations between blood cancer and genetic predisposition, including both inherited variants and acquired mutations and epimutations, have been well characterized. However, the majority of these variants affect noncoding regions, making their mechanisms difficult to hypothesize and hindering the translation of these insights into patient benefits. Fueled by unprecedented progress in next-generation sequencing and computational integrative analysis, studies have started applying combinations of epigenetic, genome architecture, and functional assays to bridge the gap between noncoding variants and blood cancer. These complementary tools have not only allowed us to understand the potential malignant role of these variants but also to differentiate key variants, cell-types, and conditions from misleading ones. Here, we briefly review recent studies that have provided fundamental insights into our understanding of how noncoding mutations at enhancers predispose and promote blood malignancies in the context of spatial genome architecture.
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http://dx.doi.org/10.3389/fimmu.2020.592087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575776PMC
October 2020

Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells.

Nat Genet 2020 11 5;52(11):1227-1238. Epub 2020 Oct 5.

Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.

Adipocyte differentiation is driven by waves of transcriptional regulators that reprogram the enhancer landscape and change the wiring of the promoter interactome. Here, we use high-throughput chromosome conformation enhancer capture to interrogate the role of enhancer-to-enhancer interactions during differentiation of human mesenchymal stem cells. We find that enhancers form an elaborate network that is dynamic during differentiation and coupled with changes in enhancer activity. Transcription factors (TFs) at baited enhancers amplify TF binding at target enhancers, a phenomenon we term cross-interaction stabilization of TFs. Moreover, highly interconnected enhancers (HICE) act as integration hubs orchestrating differentiation by the formation of three-dimensional enhancer communities, inside which, HICE, and other enhancers, converge on phenotypically important gene promoters. Collectively, these results indicate that enhancer interactions play a key role in the regulation of enhancer function, and that HICE are important for both signal integration and compartmentalization of the genome.
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http://dx.doi.org/10.1038/s41588-020-0709-zDOI Listing
November 2020

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci.

Genome Med 2020 09 25;12(1):81. Epub 2020 Sep 25.

Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.

Background: Systemic sclerosis (SSc) is a genetically complex autoimmune disease mediated by the interplay between genetic and epigenetic factors in a multitude of immune cells, with CD4+ T lymphocytes as one of the principle drivers of pathogenesis.

Methods: DNA samples exacted from CD4+ T cells of 48 SSc patients and 16 healthy controls were hybridized on MethylationEPIC BeadChip array. In parallel, gene expression was interrogated by hybridizing total RNA on Clariom™ S array. Downstream bioinformatics analyses were performed to identify correlating differentially methylated CpG positions (DMPs) and differentially expressed genes (DEGs), which were then confirmed utilizing previously published promoter capture Hi-C (PCHi-C) data.

Results: We identified 9112 and 3929 DMPs and DEGs, respectively. These DMPs and DEGs are enriched in functional categories related to inflammation and T cell biology. Furthermore, correlation analysis identified 17,500 possible DMP-DEG interaction pairs within a window of 5 Mb, and utilizing PCHi-C data, we observed that 212 CD4+ T cell-specific pairs of DMP-DEG also formed part of three-dimensional promoter-enhancer networks, potentially involving CTCF. Finally, combining PCHi-C data with SSc GWAS data, we identified four important SSc-associated susceptibility loci, TNIP1 (rs3792783), GSDMB (rs9303277), IL12RB1 (rs2305743), and CSK (rs1378942), that could potentially interact with DMP-DEG pairs cg17239269-ANXA6, cg19458020-CCR7, cg10808810-JUND, and cg11062629-ULK3, respectively.

Conclusion: Our study unveils a potential link between genetic, epigenetic, and transcriptional deregulation in CD4+ T cells of SSc patients, providing a novel integrated view of molecular components driving SSc pathogenesis.
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http://dx.doi.org/10.1186/s13073-020-00779-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519528PMC
September 2020

From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation.

Trends Immunol 2020 01 7;41(1):46-60. Epub 2019 Dec 7.

Lymphocyte Development and Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Badalona, Spain. Electronic address:

B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center B cells, plasma cells and memory B cells. Recent evidence indicates that mature B cell formation involves an essential contribution from 3D chromatin conformations through its interplay with transcription factors and epigenetic machinery. Here, we provide an up-to-date overview of the coordination between transcription factors, epigenetic changes, and chromatin architecture during terminal B cell differentiation, focusing on recent discoveries and technical advances for studying 3D chromatin structures.
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http://dx.doi.org/10.1016/j.it.2019.11.006DOI Listing
January 2020

B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation.

Leukemia 2020 04 12;34(4):1158-1162. Epub 2019 Nov 12.

Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.

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http://dx.doi.org/10.1038/s41375-019-0643-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214273PMC
April 2020

Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes.

Nat Genet 2019 07 28;51(7):1137-1148. Epub 2019 Jun 28.

Section of Epigenomics and Disease, Department of Medicine, and National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London, London, UK.

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.
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http://dx.doi.org/10.1038/s41588-019-0457-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640048PMC
July 2019

Author Correction: Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.

Nat Commun 2018 11 12;9(1):4792. Epub 2018 Nov 12.

Division of Cardiovascular Sciences, The University of Manchester, Manchester, M13 9PT, UK.

In the original version of the Article, the gene symbol for tissue factor pathway inhibitor was inadvertently given as 'TFP1' instead of 'TFPI'. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07399-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232151PMC
November 2018

Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.

Nat Commun 2018 06 28;9(1):2526. Epub 2018 Jun 28.

Division of Cardiovascular Sciences, The University of Manchester, Manchester, M13 9PT, UK.

Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation from hESCs. We also show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci (eQTLs) in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions. These findings indicate that regulatory elements in hESC-CMs identified by our approach control gene expression involved in ventricular conduction and rhythm of the heart. The study of promoter interactions in other hESC-derived cell types may be of utility in functional investigation of GWAS-associated regions.
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http://dx.doi.org/10.1038/s41467-018-04931-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023870PMC
June 2018

The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.

Nat Med 2018 06 21;24(6):868-880. Epub 2018 May 21.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.
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http://dx.doi.org/10.1038/s41591-018-0028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363101PMC
June 2018

Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Nat Commun 2017 07 13;8:16058. Epub 2017 Jul 13.

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.
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http://dx.doi.org/10.1038/ncomms16058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511350PMC
July 2017

Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes.

Nat Struct Mol Biol 2017 04 6;24(4):353-361. Epub 2017 Mar 6.

LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.

The ability of DNA double-strand breaks (DSBs) to cluster in mammalian cells has been a subject of intense debate in recent years. Here we used a high-throughput chromosome conformation capture assay (capture Hi-C) to investigate clustering of DSBs induced at defined loci in the human genome. The results unambiguously demonstrated that DSBs cluster, but only when they are induced within transcriptionally active genes. Clustering of damaged genes occurs primarily during the G1 cell-cycle phase and coincides with delayed repair. Moreover, DSB clustering depends on the MRN complex as well as the Formin 2 (FMN2) nuclear actin organizer and the linker of nuclear and cytoplasmic skeleton (LINC) complex, thus suggesting that active mechanisms promote clustering. This work reveals that, when damaged, active genes, compared with the rest of the genome, exhibit a distinctive behavior, remaining largely unrepaired and clustered in G1, and being repaired via homologous recombination in postreplicative cells.
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http://dx.doi.org/10.1038/nsmb.3387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385132PMC
April 2017

Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.

Cell 2016 11;167(5):1369-1384.e19

Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address:

Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.
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http://dx.doi.org/10.1016/j.cell.2016.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123897PMC
November 2016

IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation.

Genome Biol 2016 Jan 13;17. Epub 2016 Jan 13.

Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.

Background: The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation.

Results: Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes.

Conclusions: Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.
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http://dx.doi.org/10.1186/s13059-015-0863-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711003PMC
January 2016

The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion.

Genome Biol 2013 Jan 15;14(1):R3. Epub 2013 Jan 15.

Background: Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.

Results: We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.

Conclusions: Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.
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http://dx.doi.org/10.1186/gb-2013-14-1-r3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663113PMC
January 2013

Environmental triggers and epigenetic deregulation in autoimmune disease.

Discov Med 2011 Dec;12(67):535-45

Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

The study of epigenetic mechanisms in the pathogenesis of autoimmune diseases is receiving unprecedented attention from clinicians and researchers in the field. Autoimmune disorders comprise a wide range of genetically complex diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Together they affect a significant proportion of the population and have a great economic impact on public health systems. Epigenetic mechanisms control gene expression and are influenced by external stimuli, linking environment and gene function. A variety of environmental agents, such as viral infection, hormones, certain drugs, and pollutants, have been found to influence the development of autoimmune diseases. On the other hand, there is considerable evidence of epigenetic changes, particularly DNA methylation alterations, in diseases like systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. However, the gap in our understanding between the specific effects of external agents and the influence on epigenetic profiles has not yet been filled. Here we review a number of studies describing epigenetic alterations in autoimmune diseases and a range of environmental factors that influence the development of autoimmune diseases. We also discuss potential mechanisms linking environment and epigenetics, consider the prospects for future epigenetic studies addressing the relationship between environment and epigenetics, and comment on the use of drugs with an epigenetic-reversing effect in the clinical management of these diseases.
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December 2011

Long-range epigenetic silencing associates with deregulation of Ikaros targets in colorectal cancer cells.

Mol Cancer Res 2011 Aug 7;9(8):1139-51. Epub 2011 Jul 7.

Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, Barcelona, Spain.

Transcription factors are common targets of epigenetic inactivation in human cancer. Promoter hypermethylation and subsequent silencing of transcription factors can lead to further deregulation of their targets. In this study, we explored the potential epigenetic deregulation in cancer of Ikaros family genes, which code for essential transcription factors in cell differentiation and exhibit genetic defects in hematologic neoplasias. Unexpectedly, our analysis revealed that Ikaros undergoes very specific promoter hypermethylation in colorectal cancer, including in all the cell lines studied and around 64% of primary colorectal adenocarcinomas, with increasing proportions in advanced Duke's stages. Ikaros hypermethylation occurred in the context of a novel long-range epigenetic silencing (LRES) region. Reintroduction of Ikaros in colorectal cancer cells, ChIP-chip analysis, and validation in primary samples led us to identify a number of direct targets that are possibly related with colorectal cancer progression. Our results not only provide the first evidence that LRES can have functional specific effects in cancer but also identify several deregulated Ikaros targets that may contribute to progression in colorectal adenocarcinoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-10-0515DOI Listing
August 2011

A new epigenetic challenge: systemic lupus erythematosus.

Adv Exp Med Biol 2011 ;711:117-36

Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain.

In recent years, compelling evidence has been gathered that supports a role for epigenetic alterations in the pathogenesis of systemic lupus erythematosus (SLE). Different blood cell populations of SLE patients are characterized by a global loss of DNA methylation. This process is associated with defects in ERK pathway signalling and consequent DNMT 1 downregulation. Hypomethylation of gene promoters has been described, which permits transcriptional activation and therefore functional changes in the cells and also hypomethylation of the ribosomal RNA gene cluster. Among the identified targets undergoing demethylation are genes involved in autoreactivity (ITGAL), osmotic lysis and apoptosis (PRF1, MMP14 and LCN2), antigen presentation (CSF3R), inflammation(MMP 14), B- T-cell interaction (CD70 and CD40LG) and cytokine pathways (CSF3R, IL-4, IL-6 and IFNGR2). DNA methylation inhibitors are also known to induce autoreactivity in vitro and cause a lupus-like disease in vivo. Further, altered patterns of histone modifications have been described in SLE. CD4+ lymphocytes undergo global histone H3 and H4 deacetylation and consequent skewed gene expression. Although multiple lines of evidence highlight the contribution of epigenetic alterations to the pathogenesis of lupus in genetically predisposed individuals, many questions remain to be answered. Attaining a deeper understanding of these matters will create opportunities in the promising area of epigenetic treatments.
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http://dx.doi.org/10.1007/978-1-4419-8216-2_9DOI Listing
June 2011

Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet.

J Physiol Biochem 2011 Sep 5;67(3):463-70. Epub 2011 Apr 5.

Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, Spain.

Obesity-associated adipose tissue enlargement is characterized by an enhanced proinflammatory status and an elevated secretion of adipokines such as leptin and cytokines such as tumor necrosis factor (TNF)-alpha. Among the different mechanisms that could underlie the interindividual differences in obesity, epigenetic regulation of gene expression has emerged as a potentially important determinant. Therefore, 27 obese women (age, 32-50 years; baseline body mass index, 34.4 ± 4.2 kg/m(2)) were prescribed an 8-week low-calorie diet, and epigenetic marks were assessed. Baseline and endpoint anthropometric parameters were measured, and blood samples were drawn. Genomic DNA and RNA from adipose tissue biopsies were isolated before and after the dietary intervention. Leptin and TNF-alpha promoter methylation were measured by MSP after bisulfite treatment, and gene expression was also analyzed. Obese women with a successful weight loss (≥5% of initial body weight, n=21) improved the lipid profile and fat mass percentage (-12%, p<0.05). Both systolic (-5%, p<0.05) and diastolic (-8%, p<0.01) blood pressures significantly decreased. At baseline, women with better response to the dietary intervention showed lower promoter methylation levels of leptin (-47%, p<0.05) and TNF-alpha (-39%, p=0.071) than the non-responder group (n=6), while no differences were found between responder and non-responder group in leptin and TNF-alpha gene expression analysis. These data suggest that leptin and TNF-alpha methylation levels could be used as epigenetic biomarkers concerning the response to a low-calorie diet. Indeed, methylation profile could help to predict the susceptibility to weight loss as well as some comorbidities such as hypertension or type 2 diabetes.
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http://dx.doi.org/10.1007/s13105-011-0084-4DOI Listing
September 2011

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.

Genome Res 2010 Feb 22;20(2):170-9. Epub 2009 Dec 22.

Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08907, Spain.

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.
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http://dx.doi.org/10.1101/gr.100289.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813473PMC
February 2010

Epigenetic connections between autoimmune disorders and haematological malignancies.

Trends Immunol 2008 Dec 24;29(12):616-23. Epub 2008 Oct 24.

Cancer Epigenetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Epigenetic deregulation has become a major topic in biomedical research. Most of the information currently available in the field comes from the study of epigenetic alterations in cancer, particularly in haematological malignancies. The recognition of the epigenetic component of autoimmune diseases in conjunction with the existence of common genes underpinning pathways that are crucial to the development of autoimmunity and haematological cancers, facilitates interaction between these two areas of research. Here, we examine what is presently known from epigenetic studies of autoimmune diseases, how epigenetic alterations in haematological malignancies can be used to better understand mechanisms of epigenetic deregulation and how they might be used in epigenetic therapy to treat autoimmune diseases.
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http://dx.doi.org/10.1016/j.it.2008.08.008DOI Listing
December 2008