Pharmacoepigenetics

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.

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

Epigenetic mechanisms of importance for drug treatment.
Ivanov M, Barragan I, Ingelman-Sundberg M
Trends Pharmacol. Sci. 2014 Aug;35(8):384-96

Original articles

Single base resolution analysis of 5-hydroxymethylcytosine in 188 human genes: implications for hepatic gene expression.
Ivanov M, Kals M, Lauschke V, Barragan I, Ewels P, Käller M, et al
Nucleic Acids Res. 2016 08;44(14):6756-69

Cytostatic Effect of Repeated Exposure to Simvastatin: A Mechanism for Chronic Myotoxicity Revealed by the Use of Mesodermal Progenitors Derived from Human Pluripotent Stem Cells.
Peric D, Barragan I, Giraud-Triboult K, Egesipe AL, Meyniel-Schicklin L, Cousin C, et al
Stem Cells 2015 Oct;33(10):2936-48

Genetic and epigenetic regulation of gene expression in fetal and adult human livers.
Bonder MJ, Kasela S, Kals M, Tamm R, Lokk K, Barragan I, et al
BMC Genomics 2014 Oct;15():860

Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes.
Holmgren G, Sjögren AK, Barragan I, Sabirsh A, Sartipy P, Synnergren J, et al
Drug Metab. Dispos. 2014 Sep;42(9):1401-6

Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function.
Ivanov M, Kals M, Kacevska M, Barragan I, Kasuga K, Rane A, et al
Genome Biol. 2013 Aug;14(8):R83

CYP2W1 polymorphism: functional aspects and relation to risk for colorectal cancer.
Stenstedt K, Travica S, Guo J, Barragan I, Pors K, Patterson L, et al
Pharmacogenomics 2013 Oct;14(13):1615-22

Strong effects of environmental factors on prevalence and course of major depressive disorder are not moderated by 5-HTTLPR polymorphisms in a large Dutch sample.
Peyrot WJ, Middeldorp CM, Jansen R, Smit JH, de Geus EJ, Hottenga JJ, et al
J Affect Disord 2013 Mar;146(1):91-9

Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.
González-del Pozo M, Borrego S, Barragán I, Pieras JI, Santoyo J, Matamala N, et al
PLoS ONE 2011 ;6(12):e27894

Copy-number variations in EYS: a significant event in the appearance of arRP.
Pieras JI, Barragán I, Borrego S, Audo I, González-Del Pozo M, Bernal S, et al
Invest. Ophthalmol. Vis. Sci. 2011 Jul;52(8):5625-31

Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.
Barragán I, Borrego S, Pieras JI, González-del Pozo M, Santoyo J, Ayuso C, et al
Hum. Mutat. 2010 Nov;31(11):E1772-800

Identification of novel mutations in the ortholog of Drosophila eyes shut gene (EYS) causing autosomal recessive retinitis pigmentosa.
Abd El-Aziz MM, O'Driscoll CA, Kaye RS, Barragan I, El-Ashry MF, Borrego S, et al
Invest. Ophthalmol. Vis. Sci. 2010 Aug;51(8):4266-72

EYS is a major gene for rod-cone dystrophies in France.
Audo I, Sahel JA, Mohand-Saïd S, Lancelot ME, Antonio A, Moskova-Doumanova V, et al
Hum. Mutat. 2010 May;31(5):E1406-35

Microarray-based mutation analysis of 183 Spanish families with Usher syndrome.
Jaijo T, Aller E, García-García G, Aparisi MJ, Bernal S, Avila-Fernández A, et al
Invest. Ophthalmol. Vis. Sci. 2010 Mar;51(3):1311-7

EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa.
Abd El-Aziz MM, Barragan I, O'Driscoll CA, Goodstadt L, Prigmore E, Borrego S, et al
Nat. Genet. 2008 Nov;40(11):1285-7

Genetic analysis of FAM46A in Spanish families with autosomal recessive retinitis pigmentosa: characterisation of novel VNTRs.
Barragán I, Borrego S, Abd El-Aziz MM, El-Ashry MF, Abu-Safieh L, Bhattacharya SS, et al
Ann. Hum. Genet. 2008 Jan;72(Pt 1):26-34

Large-scale molecular analysis of a 34 Mb interval on chromosome 6q: major refinement of the RP25 interval.
Abd El-Aziz MM, Barragan I, O'Driscoll C, Borrego S, Abu-Safieh L, Pieras JI, et al
Ann. Hum. Genet. 2008 Jul;72(Pt 4):463-77

Linkage validation of RP25 Using the 10K genechip array and further refinement of the locus by new linked families.
Barragán I, Abd El-Aziz MM, Borrego S, El-Ashry MF, O'Driscoll C, Bhattacharya SS, et al
Ann. Hum. Genet. 2008 Jul;72(Pt 4):454-62

Genetic analysis of FAM46A in Spanish families with autosomal recessive retinitis pigmentosa: characterisation of novel VNTRs.
Barragán I, Borrego S, Abd El-Aziz MM, El-Ashry MF, Abu-Safieh L, Bhattacharya SS, et al
Ann. Hum. Genet. 2008 Jan;72(Pt 1):26-34

A novel genetic study of Chinese families with autosomal recessive retinitis pigmentosa.
Abd El-Aziz MM, El-Ashry MF, Chan WM, Chong KL, Barragan I, Antiñolo G, et al
Ann. Hum. Genet. 2007 May;71(Pt 3):281-94

Exclusion of four candidate genes, KHDRBS2, PTP4A1, KIAA1411 and OGFRL1, as causative of autosomal recessive retinitis pigmentosa.
Abd El-Aziz MM, Patel RJ, El-Ashry MF, Barragan I, Marcos I, Borrego S, et al
Ophthalmic Res. 2006 ;38(1):19-23

Effects of incorporated drugs on degradation of novel 2,2'-bis(2-oxazoline) linked poly(lactic acid) films.
Tarvainen T, Malin M, Barragan I, Tuominen J, Seppälä J, Järvinen K
Int J Pharm 2006 Mar;310(1-2):162-7

Mutation screening of three candidate genes, ELOVL5, SMAP1 and GLULD1 in autosomal recessive retinitis pigmentosa.
Barragan I, Marcos I, Borrego S, Antiñolo G
Int. J. Mol. Med. 2005 Dec;16(6):1163-7

Molecular genetic analysis of two functional candidate genes in the autosomal recessive retinitis pigmentosa, RP25, locus.
Abd El-Aziz MM, El-Ashry MF, Barragan I, Marcos I, Borrego S, Antiñolo G, et al
Curr. Eye Res. 2005 Dec;30(12):1081-7

Molecular analysis of RIM1 in autosomal recessive Retinitis pigmentosa.
Barragan I, Marcos I, Borrego S, Antiñolo G
Ophthalmic Res. ;37(2):89-93

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

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