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Pharmacoepigenetics

Members in Isabel Barragans research group

Our research group's ultimate goal is to understand the pharmacological response and identify new biomarkers that are amenable for targeted manipulation. Integrated analyses of genetic and epigenetic variants affecting patterns of transcription, is our strategy to comprehensibly elucidate the drivers of drug resistance and lack of drug efficacy.

Our research

We are currently characterizing somatic genetic and epigenetic mutations in the context of hepatocellular carcinoma.

Hepatocellular carcinoma is a major global tumour disease, causing more than half a million deaths every year. Unfortunately, there is a lack of effective therapies to treat it, which is due primarily to the following three reasons:

  1. There are no identified molecular biomarkers that can show the effectiveness of drugs in a selected subgroup of patients.
  2. Molecu­lar subclasses of hepatocellular carcinoma have been established using genetic biomarkers, but these do not predict responses to therapies.
  3. Multifocality has been demonstrated in patients who present with lobules with independent tumorigenic events, and both primary and recurrent tumours present with intratumour differences in mutations and cell population characteristics.

The purpose of our project is to target these specific challenges in the treatment of hepatocellular carcinoma by identifying the mechanisms of tumour response in a setting that considers all layers of regulation of gene expression. This, in conjunction with the assessment of the heterogeneity of these mechanisms between and within the different lobules and the use of patient-derived drug-resistance models, will provide a comprehensive source of mechanistic biomarkers that can be used in future drug development research and clinical management of this severe form of cancer.

Specialised methods

  • Three-dimensional cultures (and treatment/phenotyping) of primary human liver cells and cancer cell lines


    spheroids

    bioreactors
  • TET-assisted bisulfite conversion (TAB)-based determination of DNA methylation and hydroxymethylation:
  • TAB-450K (EPIC) Illumina DNA methylation arrays for genome-wide analysis of 450K/850K CpG sites
  • TAB-Methyl-Seq Agilent targeted libraries for Next Generation Sequencing
  • TAB-Sanger sequencing
  • TET-independent restriction-based determination of DNA methylation and hydroxymethylation.
  • Quantification of global DNA methylation and hydroxymethylation by mass spectrometry/liquid chromatography.
  • Smart-seq library preparation for single cell RNA-sequencing.
  • ChIP-qPCR for histone modifications in 3D liver cancer cell lines and primary hepatocyte microtissues.
  • Bioinformatics for genome-wide transcriptomic/epigenomic analyses.

Group members

Isabel Barragan Research group leader
Laura Espino Postdoc
Andre Nobre Postdoc
Shady Sayed Master thesis student

Open positions

Candidates that are interested in predoctoral and postdoctoral positions please send your personal letter and CV to Isabel Barragan, research group leader. Support for external funding applications may also be provided.

Financial support

  • European Union, Marie Curie
  • Karolinska Institutet Board of Research
  • Department of Physiology and Pharmacology
  • Carl Tryggers Stiftelse
  • Tornspiran Stiftelse
  • Svenska Läkaresällskapet
  • Varia

Publications

Reviews

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Original articles

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Recent conference communications

Oral presentation and abstract: Crossomics interactions for the identification of new biomarkers in hepatocellular carcinoma. Kasela S, Ivanov M, SayedS, Nobre A, Espino L, Marabita F, Milani L, Barragán I. Selected talk for the Emerging Researchers Forum. XXXIX Congress of SEBBM (Spanish Society of Biochemistry and Molecular Biology). Salamanca, Spain September 5-8th 2016.

Abstract: The development of TAB-Methyl-SEQ protocol for targeted profiling of 5-(hydroxy)methylcytosine with single base resolution by next-generation sequencing. Ivanov M, Kals M, Lauschke V, Barragan I, Milani L, Ingelman-Sundberg M. Gordon Research Conference on Epigenetics, Waltham, MA, USA, August 2-7, 2015.

Abstract: TAB-Methyl-SEQ protocol for targeted Next-generation sequencing of DNA (hydroxy)methylation: implications for ADME gene regulation. Ivanov M, Kals M, Lauschke V, Barragan I, Milani L, Ingelman-Sundberg M. ISSX Meeting 2015, Glasgow, UK, June 22-25, 2015.

Conference paper: Abundance and distribution of hydroxymethylcytosine (5hmC) in human liver. Ivanov M, Kals M, Kacevska M, Barragan I, Kasuga K, Rane A, Metspalu A, Milani L, Ingelman-Sundberg M. 20th International Symposium on Microsomes and Drug Oxidations, Stuttgart, Germany, May 18-25, 2014.

Abstract (Finalist of poster awards): Evaluation of a stem-cell derived in vitro system as a model for statin induced myotoxicity. Barragan I, Peric D, Laustriat D, Giraud-Triboult K, Peschanski M, Ingelman-Sundberg M. 20th International Symposium on Microsomes and Drug Oxidations. Stuttgart, Germany, May 18–22, 2014.

Abstract: The quantification and genome-wide mapping of 5- hydroxymethylcytosine in fetal and adult human livers. Ivanov M, Kals M, Kacevska M, Barragan I, Kasuga K, Rane A, Metspalu A, Milani L, Ingelman-Sundberg M. Gordon Research Conference on Epigenetics, Smithfield, MA, USA, August 4-9, 2013.

Abstract: No association between CYP2W1 variant alleles G541A (Ala181Thr) or C1463T (Pro448Leu) and colorectal cancer risk. Stenstedt K, Barragan I, Johansson I, Lindblom A, Ingelman Sundberg M, Edler D. ESCP's 7th Scientific & Annual Meeting, Vienna, September 26-28 2012.

Abstract: The hollow fiber 3D bioreactor: a tool for studies of hepatotoxicity. F Noor, D Mueller, K Zeilinger, I Barragan, I Johansson, P Gunness, L Sivertsson, E Heinzle, M Ingelman-Sundberg. SEURAT (Towards the replacement of in vivo repeated dose systemic toxicity testing)-1 - 2nd Annual meeting, Lisbon, Portugal, February 8-9 2012

Published abstract: Mutation screening of multiple genes in Spanish patients with Autosomal Recessive Retinitis Pigmentosa using a Custom designed Resequencing microarray. González-Del Pozo M, Pieras J, Barragán I, Naranjo B, Matamala N, Borrego S, Antiñolo G. European Human Genetics Conference 2011. European Journal of Human Genetics 19, 380 ISSN/ISBN: 1018-4813 Amsterdam, the Netherlands, May 38-31 2011.

Published abstract: Novel study of copy number variations in EYS using the multiple ligation-dependent probe amplification (MLPA) technique. Pieras J, Barragán I, González-Del Pozo M, Matamala N, Audo I, Bernal S, Baiget M, Zeitz C, Bhattacharya S, Borrego S, Antiñolo G. European Human Genetics Conference 2011. European Journal of Human Genetics 19, 380 ISSN/ISBN: 1018-4813 Amsterdam, the Netherlands, May 38-31 2011.

Published abstract: Haplotype analysis of EYS mutations identified in different European populations. Barragán I, Matamala N, González-Del Pozo M, Pieras J, Littink K, Cremers F, Borrego S, Antiñolo G. European Human Genetics Conference 2011. European Journal of Human Genetics 19, 380 ISSN/ISBN: 1018-4813 Amsterdam, the Netherlands, May 38-31 2011.

Published commentaries

News and views on the published article

EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Photoreceptors in evolution and disease.
Cook B, Zelhof AC. Nat Genet. 2008 Nov;40(11):1275-6. doi: 10.1038/ng1108-1275.

Collaborations

International collaborators

  • Dr Carmen Saez (Pathologist and group leader of Endocrine Tumorigenesis and Hormonal Regulation of Cancer at the Institute of Biomedicine of Seville, Spain): anticancer therapy resistance phenotyping and proteomics.
  • Dr Hua You (Oncologist and Assistant Professor at the Department of Oncology of the Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China): circulating DNA biomarkers of cancer.
  • Dr Lili Milani (Senior Researcher and Head of Genotyping and Sequencing Core Facility, Estonian Genome Center): bioinformatics for NGS-based epigenomic analyses.

National collaborators

  • Dr Jorge Ruas (Associate Professor and group leader of the group Molecular and Cellular Exercise Physiology at the Department of Physiology and Pharmacology, Karolinska Institutet): isoform-specific transcriptional reprogramming

Contact us

Forskarassistent

Isabel Barragan

Telefon: 08-524 822 71
Enhet: Barragan Isabel grupp - Farmakoepigenetik
E-post: isabel.barragan@ki.se