Imperial College London

DrInesCebola

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Advanced Research Fellow
 
 
 
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Contact

 

i.dos-santos-cebola Website

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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23 results found

Cebola I, 2021, Deletion of regulatory elements with all-in-one CRISPR-Cas9 vectors, Enhancers and Promoters - Methods and Protocols, Editors: Benetto, Tilman, Publisher: Springer Nature

Loss-of-function experiments are essential for the functional investigation of cis-regulatory elements (CREs), such as transcriptional enhancers. This can be achieved with CRISPR-Cas9 using pairs of single guide RNAs (sgRNAs) to target the flanking regions of a CRE. Here, I describe a single-step protocol to rapidly and inexpensively generate vectors co-expressing two sgRNAs, which allows re-usage of gRNAs oligonucleotides from one experimental design to another. This protocol is applicable to cloning sgRNAs into virtually any CRISPR-Cas9 backbone that allows cloning by Golden Gate, by adapting the primer design.

Book chapter

Maude H, Sanchez Cabanillas C, Cebola I, 2021, Epigenetics of hepatic insulin resistance, Frontiers in Endocrinology, Vol: 12, Pages: 1-24, ISSN: 1664-2392

Insulin resistance (IR) is largely recognized as a unifying feature that underlies metabolic dysfunction. Both lifestyle and genetic factors contribute to IR. Work from recent years has demonstrated that the epigenome may constitute an interface where different signals may converge to promote IR gene expression programs. Here, we review the current knowledge of the role of epigenetics in hepatic IR, focusing on the roles of DNA methylation and histone post-translational modifications. We discuss the broad epigenetic changes observed in the insulin resistant liver and its associated pathophysiological states and leverage on the wealth of ‘omics’ studies performed to discuss efforts in pinpointing specific loci that are disrupted by these changes. We envision that future studies, with increased genomic resolution and larger cohorts, will further the identification of biomarkers of early onset hepatic IR and assist the development of targeted interventions. Furthermore, there is growing evidence to suggest that persistent epigenetic marks may be acquired over prolonged exposure to disease or deleterious exposures, highlighting the need for preventative medicine and long-term lifestyle adjustments to avoid irreversible or long-term alterations in gene expression.

Journal article

Hu M, Cebola I, Carrat G, Jiang S, Nawaz S, Khamis A, Canouil M, Froguel P, Schulte A, Solimena M, Ibberson M, Marchetti P, Cardenas-Diaz FL, Gadue PJ, Hastoy B, Almeida-Souza L, McMahon H, Rutter GAet al., 2021, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion., Cell Research, Vol: 34, Pages: 1-1, ISSN: 1001-0602

Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.

Journal article

Hu M, Cebola I, Carrat G, Nawaz S, Khamis A, Canouil M, Froguel P, Schulte A, Solimena M, Ibberson M, Marchetti P, Gadue P, Hastoy B, McMahon H, Rutter Get al., 2020, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion, Publisher: SPRINGER

Working paper

Cebola I, 2020, Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease, Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol: 12, Pages: 1-29, ISSN: 1939-005X

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) result from complex interactions between intrinsic and extrinsic factors, including genetics and exposure to obesogenic environments. These risk factors converge in aberrant gene expression patterns in the liver, which are underlined by altered cis-regulatory networks. In homeostasis and in disease states, liver cis-regulatory networks are established by coordinated action of liver-enriched transcription factors (TFs), which define enhancer landscapes, activating broad gene programs with spatiotemporal resolution. Recent advances in DNA sequencing have dramatically expanded our ability to map active transcripts, enhancers and TF cistromes, and to define the 3D chromatin topology that contains these elements. Deployment of these technologies has allowed investigation of the molecular processes that regulate liver development and metabolic homeostasis. Moreover, genomic studies of NAFLD patients and NAFLD models have demonstrated that the liver undergoes pervasive regulatory rewiring in NAFLD, which is reflected by aberrant gene expression profiles. We have therefore achieved an unprecedented level of detail in the understanding of liver cis-regulatory networks, particularly in physiological conditions. Future studies should aim to map active regulatory elements with added levels of resolution, addressing how the chromatin landscapes of different cell lineages contribute to and are altered in NAFLD and NAFLD-associated metabolic states. Such efforts would provide additional clues into the molecular factors that trigger this disease. This article is categorized under: Biological Mechanisms > Metabolism Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > Genetic/Genomic Methods.

Journal article

Cebola I, 2019, Pancreatic Islet Transcriptional Enhancers and Diabetes, Current Diabetes Reports, Vol: 19, ISSN: 1534-4827

<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose of Review</jats:title><jats:p>Common genetic variants that associate with type 2 diabetes risk are markedly enriched in pancreatic islet transcriptional enhancers. This review discusses current advances in the annotation of islet enhancer variants and their target genes.</jats:p></jats:sec><jats:sec><jats:title>Recent Findings</jats:title><jats:p>Recent methodological advances now allow genetic and functional mapping of diabetes causal variants at unprecedented resolution. Mapping of enhancer-promoter interactions in human islets has provided a unique appreciation of the complexity of islet gene regulatory processes and enabled direct association of noncoding diabetes risk variants to their target genes.</jats:p></jats:sec><jats:sec><jats:title>Summary</jats:title><jats:p>The recently improved human islet enhancer annotations constitute a framework for the interpretation of diabetes genetic signals in the context of pancreatic islet gene regulation. In the future, integration of existing and yet to come regulatory maps with genetic fine-mapping efforts and in-depth functional characterization will foster the discovery of novel diabetes molecular risk mechanisms.</jats:p></jats:sec>

Journal article

Cebola I, Miguel-Escalada I, Bonas-Guarch S, Ponsa-Cobas J, Atla G, Javierre B, Ravassard P, Fraser P, Ferrer Jet al., 2019, Unravelling of new type 2 diabetes genes with 3D chromatin topology analysis and CRISPR-Cas9 perturbations, BES 2019, ISSN: 1470-3947

Genome-wide association studies have identified nearly 250 loci carrying genetic variants associated with type 2 diabetes (T2D) susceptibility, which are often located within pancreatic islet transcriptional enhancers. Due to the complex nature of transcriptional enhancers, assigning risk variants to true disease susceptibility effector genes has remained a challenge. In this study, we applied promoter capture Hi-C to create a genome-wide map of promoter-enhancer interactions in adult human pancreatic islets. We then set out to investigate which genes are regulated by enhancers carrying T2D risk variants, observing that T2D variants often interact with more than one gene, and that, unlike what has been assumed until now, the nearest genes are not always the true targets of T2D susceptibility variants. We validated our in silico predictions by applying CRISPR-Cas9-based methods to perturb T2D enhancers in the human pancreatic ß cell line EndoC-ßH3, demonstrating that the detected enhancer-promoter interactions reflect functional chromatin interactions in human islets. This study reveals 3D chromatin architecture analysis coupled with genome editing as a powerful framework for interpretation of T2D genetic association signals. Furthermore, the results shed light into unexpected regulatory links that may affected by T2D susceptibility variants, bringing to our attention new players in T2D aetiology.

Conference paper

Cheung R, Pizza G, Nguyen-Tu M-S, Chabosseau P, Rolando D, Cebola I, Marchetti P, Shapiro J, Piemonti L, Sakamoto K, Smith D, Rutter G, Martinez-Sanchez Aet al., 2019, Glucose-controlled miR-125b regulates beta cell function, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S219-S219, ISSN: 0012-186X

Conference paper

Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G, Javierre BM, Rolando DMY, Farabella I, Morgan CC, García-Hurtado J, Beucher A, Morán I, Pasquali L, Ramos-Rodríguez M, Appel EVR, Linneberg A, Gjesing AP, Witte DR, Pedersen O, Grarup N, Ravassard P, Torrents D, Mercader JM, Piemonti L, Berney T, de Koning EJP, Kerr-Conte J, Pattou F, Fedko IO, Groop L, Prokopenko I, Hansen T, Marti-Renom MA, Fraser P, Ferrer Jet al., 2019, Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes., Nature genetics, Vol: 51, Pages: 1137-1148, ISSN: 1061-4036

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.

Journal article

Beucher A, Cebola I, 2019, One-step dual CRISPR/Cas9 guide RNA cloning protocol, Publisher: Protocol Exchange

Existing protocols for dual guide RNA cloning rely on synthesised DNA oligonucleotides of >100 bp that contain both guide RNA sequences, and are therefore not reusable in alternative experimental designs. Here, we describe a single-step protocol to rapidly and inexpensively generate vectors expressing two guide RNAs (gRNAs) simultaneously, which allows re-usage of gRNAs oligonucleotides from one experimental design to another. This protocol is applicable to cloning gRNAs into virtually any CRISPR/Cas9 backbone that allows cloning by Golden Gate, by adapting the primer design. Here, we provide details for cloning gRNAs into vectors with BbsI and BsmBI sites, two of the most frequently found enzymes in CRISPR/Cas9 gRNA expression cassettes.This protocol has been successfully applied to delete pancreatic islet enhancers that harbour type 2 diabetes variants and to validate enhancer-promoter interactions (Miguel-Escalada et al., Nature Genetics 2019).In the future, we foresee that this simple protocol may also be applied to target coding sequences, as well as to target other important kinds of noncoding regulatory elements, including lncRNAs, miRNAs, and chromatin structural anchor points.

Working paper

De Vas MG, Garstang MG, Joshi SS, Khan TN, Atla G, Parry D, Moore D, Cebola I, Zhang S, Cui W, Lampe AK, Lam WW, FitzPatrick DR, Ferrer J, Pradeepa MM, Atanur SSet al., 2019, De novo variants in population constrained fetal brain enhancers and intellectual disability, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. <jats:italic>De novo</jats:italic> mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We sequenced 70 whole genomes from 24 ID probands and their unaffected parents and analyzed 30 previously sequenced genomes from exome-negative ID probands.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We found that DNVs were selectively enriched in fetal brain-specific enhancers that show purifying selection in human population. DNV containing enhancers were associated with genes that show preferential expression in the pre-frontal cortex, have been previously implicated in ID or related disorders, and exhibit intolerance to loss of function variants. DNVs from ID probands preferentially disrupted putative binding sites of neuronal transcription factors, as compared to DNVs from healthy individuals and most showed allele-specific enhancer activity. In addition, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (<jats:italic>CSMD1</jats:italic>, <jats:italic>OLFM1</jats:italic> and <jats:italic>POU3F3)</jats:italic>. Moreover, CRISPR-based perturbation of a DNV-containing enhancer caused <jats:italic>CSMD1</jats:italic> overexpression and abnormal expression of neurodevelopmental regulators.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our results, therefore, provide new evidence to indicate that DNVs in constrained fetal brain-speci

Working paper

Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani H-A, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, MacKenzie Ross RV, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Vonk Noordegraaf A, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët D-A, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, Wilkins MRet al., 2019, Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis, The Lancet Respiratory Medicine, Vol: 7, Pages: 227-238, ISSN: 2213-2600

Journal article

Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Joan P-C, Mendieta-Esteban J, Rolando DMY, Javierre B, Atla G, Farabella I, Morgan C, García-Hurtado J, Beucher A, Morán I, Pasquali L, Ramos M, Appel EVR, Linneberg A, Gjesing A, Witte D, Pedersen O, Grarup N, Ravassard P, Torrents D, Mercader JM, Piemonti L, Berney T, Koning de EJP, Kerr-Conte J, Pattou F, Fedko I, Prokopenko I, Hansen T, Marti-Renom M, Fraser P, Ferrer Jet al., 2018, Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes

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 regions (enhancer clusters, stretch enhancers or super-enhancers). So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in 3D-space. Furthermore, their target genes are generally unknown. We have now created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers with their target genes, often located hundreds of kilobases away. It further revealed sets of islet enhancers, super-enhancers and active promoters that form 3D higher-order hubs, some of which show coordinated glucose-dependent activity. Hub genetic variants impact the heritability of insulin secretion, and help identify individuals in whom genetic variation of islet function is important for T2D. Human islet 3D chromatin architecture thus provides a framework for interpretation of T2D GWAS signals.

Working paper

Martinez-Sanchez A, Nguyen-Tu M-S, Cebola I, Yavari A, Marchetti P, Piemonti L, de Koning E, Shapiro AMJ, Johnson P, Sakamoto K, Smith DM, Leclerc I, Ashrafian H, Ferrer J, Rutter GAet al., 2018, MiR-184 expression is regulated by AMPK in pancreatic islets., FASEB Journal, Vol: 32, Pages: 2587-2600, ISSN: 0892-6638

AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β-cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits (βAMPKdKO mice) impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β-cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β-cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.

Journal article

Martinez-Sanchez A, Nguyen-Tu MS, Cebola I, Yavari A, Marchetti P, Piemonti L, Leclerc I, Sakamoto K, Smith DM, Rutter GAet al., 2018, Adenosine Monophosphate (AMP)-activated protein kinase (AMPK) regulates the expression of miR-184 and other miRNAs important for beta cell function, Publisher: WILEY, Pages: 48-48, ISSN: 0742-3071

Conference paper

Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Girerd B, Arora A, Knight J, Hanscombe K, Karnes J, Kaakinen M, Gall HH, Ulrich A, Harbaum L, Aman J, Cebola I, Ferrer J, Martin L, He H, Frost AE, White R, Lutz K, Walsworth A, Wharton J, Lawrie A, Humbert M, Soubrier F, Tregouet D, Prokopenko I, Kittles R, Graef S, Nichols WC, Trembath R, Desai AA, Morrell N, Wilkins Met al., 2018, Genetic Determinants of Risk and Survival in Pulmonary Arterial Hypertension, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Cebola I, Pasquali L, 2016, Non-coding genome functions in diabetes, Journal of Molecular Endocrinology, Vol: 56, Pages: R1-R20, ISSN: 1479-6813

Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, high-throughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well-studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell-type specific and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and non-functional non-coding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the non-coding regulatory landscape of the pancreatic endocrine cells and provide an overview of the recent developments in this field.

Journal article

Cebola I, Custodio J, Munoz M, Diez-Villanueva A, Pare L, Prieto P, Ausso S, Coll-Mulet L, Bosca L, Moreno V, Peinado MAet al., 2015, Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE(2) in colorectal cancer, Clinical Epigenetics, Vol: 7, ISSN: 1868-7083

BackgroundMisregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells.ResultsData from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E2 (PGE2) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors.ConclusionsThe transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies.

Journal article

Cebola I, Rodríguez-Seguí SA, Cho CH-H, Bessa J, Rovira M, Luengo M, Chhatriwala M, Berry A, Ponsa-Cobas J, Maestro MA, Jennings RE, Pasquali L, Morán I, Castro N, Hanley NA, Gomez-Skarmeta JL, Vallier L, Ferrer Jet al., 2015, TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors, Nature Cell Biology, Vol: 17, Pages: 615-626, ISSN: 1465-7392

Journal article

Pasquali L, Gaulton KJ, Rodriguez-Segui SA, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Moran I, Gomez-Marin C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, Garcia-Hurtado J, Angel Maestro M, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Luis Gomez-Skarmeta J, Mueller F, McCarthy MI, Ferrer Jet al., 2014, Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants, Nature Genetics, Vol: 46, Pages: 136-+, ISSN: 1546-1718

Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.

Journal article

Weedon MN, Cebola I, Patch A-M, Flanagan SE, De Franco E, Caswell R, Rodríguez-Seguí SA, Shaw-Smith C, Cho CH-H, Allen HL, Houghton JA, Roth CL, Chen R, Hussain K, Marsh P, Vallier L, Murray A, International Pancreatic Agenesis Consortium, Ellard S, Ferrer J, Hattersley ATet al., 2014, Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis., Nature genetics, Vol: 46, Pages: 61-64, ISSN: 1061-4036

The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ~400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.

Journal article

Cebola I, Peinado MA, 2012, Epigenetic deregulation of the COX pathway in cancer, PROGRESS IN LIPID RESEARCH, Vol: 51, Pages: 301-313, ISSN: 0163-7827

Journal article

Silva A, Girio A, Cebola I, Santos CI, Antunes F, Barata JTet al., 2011, Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells, LEUKEMIA, Vol: 25, Pages: 960-967, ISSN: 0887-6924

Journal article

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