Biola M. Javierre

Josep Carreras Leukaemia Research Institute

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Peter Fraser

Florida State University

Mikhail Spivakov

Imperial College London

Steven W. Wingett

Babraham Institute

Esteban Ballestar

East China Normal University

Jonathan Cairns

AstraZeneca (United Kingdom)

Mattia Frontini

National Health Service

Alfonso Valencia

Barcelona Supercomputing Center

Chris Wallace

MRC Biostatistics Unit

Kate Downes

University of Cambridge

Frances Burden

University of Cambridge

Cooperative Institutions

University of Cambridge

Josep Carreras Leukaemia Research Institute

Universitat de Barcelona

Institut d'Investigació Biomédica de Bellvitge

Instituto de Salud Carlos III

National Institute for Health Research

Pompeu Fabra University

Wellcome Sanger Institute

Centro de Investigación Biomédica en Red de Cáncer

National Health Service

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Environmental triggers and epigenetic deregulation in autoimmune disease.

PubMed (2011)

Biola M. Javierre Henar Hernando Esteban Ballestar

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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Citations (113)

The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

Cell (2016)

H.G. Stunnenberg Martin Hirst Sergio Abrignani David J. Adams Melanie de Almeida

Epigenome

Blueprint

Scientific discovery

10.1016/j.cell.2016.11.007

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Citations (482)

An Integrated Workflow to Study the Promoter-Centric Spatio-Temporal Genome Architecture in Scarce Cell Populations

Journal of Visualized Experiments (2023)

Llorenç Rovirosa Laureano Tomás-Daza Blanca Urmeneta Alfonso Valencia Biola M. Javierre

Spatiotemporal gene transcription is tightly regulated by distal regulatory elements, such as enhancers and silencers, which rely on physical proximity with their target gene promoters to control transcription. Although these regulatory elements are easy to identify, their target genes are difficult to predict, since most of them are cell-type specific and may be separated by hundreds of kilobases in the linear genome sequence, skipping over other non-target genes. For several years, Promoter Capture Hi-C (PCHi-C) has been the gold standard for the association of distal regulatory elements to their target genes. However, PCHi-C relies on the availability of millions of cells, prohibiting the study of rare cell populations such as those commonly obtained from primary tissues. To overcome this limitation, low input Capture Hi-C (liCHi-C), a cost-effective and customizable method to identify the repertoire of distal regulatory elements controlling each gene of the genome, has been developed. liCHi-C relies on a similar experimental and computational framework as PCHi-C, but by employing minimal tube changes, modifying the reagent concentration and volumes, and swapping or eliminating steps, it accounts for minimal material loss during library construction. Collectively, liCHi-C enables the study of gene regulation and spatiotemporal genome organization in the context of developmental biology and cellular function.

10.3791/65316

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Citations (1)

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

Trends in Immunology (2019)

Alba Azagra Ester Marina-Zárate Almudena R. Ramiro Biola M. Javierre Maribel Parra

Transcription

10.1016/j.it.2019.11.006

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Citations (21)

NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLL-r B-ALL by regulating NR3C1 expression

Blood (2024)

Belén López‐Millán Alba Rubio-Gayarre Meritxell Vinyoles Juan L. Trincado Mario F. Fraga

10.1182/blood.2023022050

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Insights into the human cDNA: A descriptive study using library screening in yeast

Journal of Genetic Engineering and Biotechnology (2024)

Zina Alaswad Nayera E Attallah Basma Aboalazm Eman S Elmeslhy Asmaa S. Mekawy

The utilization of human cDNA libraries in yeast genetic screens is an approach that has been used to identify novel gene functions and/or genetic and physical interaction partners through forward genetics using yeast two-hybrid (Y2H) and classical cDNA library screens. Here, we summarize several challenges that have been observed during the implementation of human cDNA library screens in Saccharomyces cerevisiae (budding yeast). Upon the utilization of DNA repair deficient-yeast strains to identify novel genes that rescue the toxic effect of DNA-damage inducing drugs, we have observed a wide range of transcripts that could rescue the strains. However, after several rounds of screening, most of these hits turned out to be false positives, most likely due to spontaneous mutations in the yeast strains that arise as a rescue mechanism due to exposure to toxic DNA damage inducing-drugs. The observed transcripts included mitochondrial hits, non-coding RNAs, truncated cDNAs, and transcription products that resulted from the internal priming of genomic regions. We have also noticed that most cDNA transcripts are not fused with the GAL4 activation domain (GAL4AD), rendering them unsuitable for Y2H screening. Consequently, we utilized Sanger sequencing to screen 282 transcripts obtained from either four different yeast screens or through direct fishing from a human kidney cDNA library. The aim was to gain insights into the different transcription products and to highlight the challenges of cDNA screening approaches in the presence of a significant number of undesired transcription products. In summary, this study describes the challenges encountering human cDNA library screening in yeast as a valuable technique that led to the identification of important molecular mechanisms. The results open research venues to further optimize the process and increase its efficiency.

Descriptive research

10.1016/j.jgeb.2024.100427

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MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex

Proceedings of the National Academy of Sciences (2021)

Paula Llabata Manuel Torres-Diz Antonio Gómez Laureano Tomás-Daza Octavio A. Romero

The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.

10.1073/pnas.2024824118

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Citations (10)

Additional file 3: of Integrating epigenomic data and 3D genomic structure with a new measure of chromatin assortativity

Figshare (2016)

Véra Pancaldi Enrique Carrillo de Santa Pau Biola M. Javierre David Juan Peter Fraser

A tab-formatted text file containing the calculated values of abundance and ChAs for all features in all four networks. (TXT 23 kb)

Epigenomics

Assortativity

10.6084/m9.figshare.c.3617615_d3

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Citations (0)

Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes

Cell Reports (2023)

Olga Mielczarek Carolyn H. Rogers Yinxiu Zhan Louise S. Matheson Michael J. T. Stubbington

To produce a diverse antibody repertoire, immunoglobulin heavy-chain (Igh) loci undergo large-scale alterations in structure to facilitate juxtaposition and recombination of spatially separated variable (VH), diversity (DH), and joining (JH) genes. These chromosomal alterations are poorly understood. Uncovering their patterns shows how chromosome dynamics underpins antibody diversity. Using tiled Capture Hi-C, we produce a comprehensive map of chromatin interactions throughout the 2.8-Mb Igh locus in progenitor B cells. We find that the Igh locus folds into semi-rigid subdomains and undergoes flexible looping of the VH genes to its 3′ end, reconciling two views of locus organization. Deconvolution of single Igh locus conformations using polymer simulations identifies thousands of different structures. This heterogeneity may underpin the diversity of V(D)J recombination events. All three immunoglobulin loci also participate in a highly specific, developmentally regulated network of interchromosomal interactions with genes encoding B cell-lineage factors. This suggests a model of interchromosomal coordination of B cell development.

Chromosome conformation capture

Immunoglobulin heavy chain

10.1016/j.celrep.2023.113074

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Citations (2)

Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Stephen M. Watt Louella Vasquez Klaudia Walter Alice Mann Kousik Kundu

Abstract Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity 1 , and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases 2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.

10.1101/620260

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Citations (1)