Profile picture Stefan Barakat
Researcher

T.S. (Stefan) Barakat, MD PhD

Clinical Genetics

  • Department
  • Clinical Genetics
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About

Introduction

My lab focusses on deciphering the role of the non-coding genome in gene regulation, with a focus on human embryonic stem cells and neurodevelopment. As many genetic disorders of brain development cannot at present be explained by routine genetic diagnostics, we anticipate that many of these disorders are caused by alterations of non-coding elements, including enhancers. Using state-of-the-art methods such as brain organoids, epigenome characterization and functional genomics, we are characterizing the contribution of the non-coding genome to brain disorders, ultimately aiming for novel diagnostic tools that will benefit patients. 

Education and career

During my PhD research period I discovered the X-linked Rnf12 gene as an essential activator of X-chromosome inactivation (XCI), a crucial epigenetic mechanism during female embryonic development (Cell 2009, PLoS Genetics 2011). 

My postdoctoral work has focused on understanding the pluripotency-network in embryonic stem cells, from a perspective of enhancer regulation by pluripotency TFs and histone modifications. 

I recently returned to the Erasmus MC to start my own laboratory at the department of Clinical Genetics. Here my research focusses on deciphering the role of the non-coding genome in genetic disorders, with a particular focus on brain disorders.

My group recently discovered a novel type of severe epilepsy and developmental delay. This novel genetic disorder is caused by mutations of the UGP2  gene. We currently focus on therapy development for this new disorder. 

Publications

Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly and epilepsy.
Mohammed AlMuhaizea, Rawan AlMass, Aljouhra AlHargan, Anoud AlBader, Eva Medico Salsench, Jude Howaidi, Jacie Ihinger, Peter Karachunski, Amber Begtrup, Monica Segura Castell, Peter Bauer, Aida Bertoli-Avella, Ibrahim H. Kaya, Jumanah AlSufayan, Laila AlQuait, Azizah Chedrawi, Stefan T. Arold, Dilek Colak, Tahsin Stefan Barakat , Namik Kaya. (2020). Acta Neuropathol. 2020 Jan 31.

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.
Hengel H, Bosso-Lefèvre C, Grady G, Szenker-Ravi E, Li H, Pierce S, Lebigot E, Tan TT, Eio M, Narayanan G, Utami K, Yau M, Handal N, Deigendesch W, Keimer R, Marzouqa H, Gunay-Aygun M, Muriello M, Verhelst H, Weckhuysen S, Mahida S, Naidu S, Thomas T, Ying Lim J, Shien Tan E, Haye D, Willemsen M, Oegema R, Mitchell W, Pierson T, Andrews M, Willing M, Rodan L, Barakat TS, van Slegtenhorst M, Gavrilova R, Martinelli D, Gilboa T, Tamim A, Hashem M, AlSayed M, Abdulrahim M, Al-Owain M, Awaji A, Mahmoud A, Faqeih E, Al Asmar Ai, Algain S, Jad L,Aldhalaan H, Helbig I, Koolen D, Riess A, Kraegeloh-Mann I, Bauer P, Gulsuner S, Stamberger H, Ng A, Tang S, Tohari S, Keren B, Schultz-Rogers L, Klee E, Barresi S, Tartaglia M, Mor-Shaked H, Maddirevula S, Begtrup A, Telegraf Ai, Pfundt R, Schule R, Ciruna B, Bonnard C, Pouladi M, Stewart J, Claridge-Chang A, J Lefeber D, Alkuraya F, Mathuru A, Venkatesh B, Barycki J, Simpson M, Jamuar S, Schöls L and Reversade B. (2020). Nat Commun. 2020 Jan 30;11(1):595.

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.
Perenthaler E, Nikoncuk A, Yousefi S, Berdowski WM, Alsagob M, Capo I, van der Linde HC, van den Berg P, Jacobs EH, Putar D, Ghazvini M, Aronica E, van IJcken WFJ, de Valk WG, Medici-van den Herik E, van Slegtenhorst M, Brick L, Kozenko M, Kohler JN, Bernstein JA, Monaghan KG, Begtrup A, Torene R, Al Futaisi A, Al Murshedi F, Mani R, Al Azri F, Kamsteeg EJ, Mojarrad M, Eslahi A, Khazaei Z, Darmiyan FM, Doosti M, Karimiani EG, Vandrovcova J, Zafar F, Rana N, Kandaswamy KK, Hertecant J, Bauer P, AlMuhaizea MA, Salih MA, Aldosary M, Almass R, Al-Quait L, Qubbaj W, Coskun S, Alahmadi KO, Hamad MHA, Alwadaee S, Awartani K, Dababo AM, Almohanna F, Colak D, Dehghani M, Mehrjardi MYV, Gunel M, Ercan-Sencicek AG, Passi GR, Cheema HA, Efthymiou S, Houlden H, Bertoli-Avella AM, Brooks AS, Retterer K, Maroofian R, Kaya N, van Ham TJ, Barakat TS. (2019). Acta Neuropathol. 2019 Dec 9.

De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy.
Nabais Sá MJ, Venselaar H, Wiel L, Trimouille A, Lasseaux E, Naudion S, Lacombe D, Piton A, Vincent-Delorme C, Zweier C, Reis A, Trollmann R, Ruiz A, Gabau E, Vetro A, Guerrini R, Bakhtiari S, Kruer MC, Amor DJ, Cooper MS, Bijlsma EK, Barakat TS, van Dooren MF, van Slegtenhorst M, Pfundt R, Gilissen C, Willemsen MA, de Vries BBA, de Brouwer APM, Koolen DA. (2019). Genet Med. 2019 Nov 28.

Building Bridges Between the Clinic and the Laboratory: A Meeting Review – Brain Malformations: A Roadmap for Future Research.
Tamar Sapir, Tahsin Stefan Barakat, Mercedes F. Paredes, Tally Lerman-Sagie, Eleonora Aronica, Wlodzimierz Klonowski, Laurent Nguyen, Bruria Ben Zeev, Nadia Bahi-Buisson, Richard Leventer, Noa Rachmian and Orly Reiner. (2019). Front. Cell. Neurosci., 27 September 2019.

Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development.
Elena Perenthaler, Soheil Yousefi, Eva Niggl and Tahsin Stefan Barakat. (2019). Front. Cell. Neurosci., 31 July 2019.

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.
Jolly A, Bayram Y, Turan S, Aycan Z, Tos T, Abali ZY, Hacihamdioglu B, Coban Akdemir ZH, Hijazi H, Bas S, Atay Z, Guran T, Abali S, Bas F, Darendeliler F, Colombo R, Barakat TS, Rinne T1, White JJ, Yesil G, Gezdirici A, Gulec EY, Karaca E, Pehlivan D, Jhangiani SN, Muzny DM, Poyrazoglu S, Bereket A, Gibbs RA, Posey JE, Lupski JR. (2019). J Clin Endocrinol Metab. 2019 Aug 1;104(8):3049-3067.

The evolution of Great Apes has shaped the functional enhancers' landscape in human embryonic stem cells.
Glinsky G, Barakat TS. (2019). Stem Cell Res. 2019 May;37:101456.

REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.
Gontan C, Mira-Bontenbal H, Magaraki A, Dupont C, Barakat TS, Rentmeester E, Demmers J, Gribnau J. (2018). Nat Commun. 2018 Nov 12;9(1):4752.

Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells.
Tahsin Stefan Barakat, Florian Halbritter, Man Zhang, André F. Rendeiro, Elena Perenthaler, Christoph Bock, and Ian Chambers. (2018). Cell Stem Cell. 2018 Aug 2; 23(2): 276–288.e8.

Dynamics of gene silencing during X inactivation using allele-specific RNA-seq.
Marks H, Kerstens HH, Barakat TS, Splinter E, Dirks RA, van Mierlo G, Joshi O, Wang SY, Babak T, Albers CA, Kalkan T, Smith A, Jouneau A, de Laat W, Gribnau J, Stunnenberg HG. (2015). Genome Biol. 2015 Aug 3;16:149.

Stable X chromosome reactivation in female human induced pluripotent stem cells.
Barakat TS, Ghazvini M, de Hoon B, Li T, Eussen B, Douben H, van der Linden R, van der Stap N, Boter M, Laven JS, Galjaard RJ, Grootegoed JA, de Klein A, Gribnau J. (2015). Stem Cell Reports. 2015 Feb 10;4(2):199-208.

Generation of knockout alleles by RFLP based BAC targeting of polymorphic embryonic stem cells.
Tahsin Stefan Barakat and Joost Gribnau. (2015). Methods Mol Biol. 2015;1227:143-80.

Combined DNA-RNA fluorescent in situ hybridization (FISH) to study X chromosome inactivation in differentiated female mouse embryonic stem cells.
Barakat TS, Gribnau J. (2014). J Vis Exp. 2014 Jun 14;(88).

The trans-activator RNF12 and cis-acting elements effectuate X chromosome inactivation independent of X-pairing.
Barakat TS, Loos F, van Staveren S, Myronova E, Ghazvini M, Grootegoed JA, Gribnau J. (2014). Mol Cell. 2014 Mar 20;53(6):965-78.

Structural and numerical changes of chromosome X in patients with esophageal atresia.
Brosens E, de Jong EM, Barakat TS, Eussen BH, D'haene B, De Baere E, Verdin H4, Poddighe PJ, Galjaard RJ, Gribnau J, Brooks AS, Tibboel D, de Klein A. (2014). Eur J Hum Genet. 2014 Sep;22(9):1077-84.

The pluripotency factor-bound intron 1 of Xist is dispensable for X chromosome inactivation and reactivation in vitro and in vivo.
Minkovsky A, Barakat TS, Sellami N, Chin MH, Gunhanlar N, Gribnau J, Plath K. (2013). Cell Rep. 2013 Mar 28;3(3):905-18.

X chromosome inactivation in the cycle of life.
Barakat TS, Gribnau J. (2012). Development. 2012 Jun;139(12):2085-9.

RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation.
Gontan C, Achame EM, Demmers J, Barakat TS, Rentmeester E, van IJcken W, Grootegoed JA, Gribnau J. (2012). Nature. 2012 Apr 29;485(7398):386-90.

RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation.
Zhang L, Huang H, Zhou F, Schimmel J, Pardo CG, Zhang T, Barakat TS, Sheppard KA, Mickanin C, Porter JA, Vertegaal AC, van Dam H, Gribnau J, Lu CX, ten Dijke P. Mol Cell. 2012 Jun 8;46(5):650-61.

Precise BAC targeting of genetically polymorphic mouse ES cells.
Barakat TS, Rentmeester E, Sleutels F, Grootegoed JA, Gribnau J. (2011). Nucleic Acids Res. 2011 Oct;39(18):e121.

RNF12 activates Xist and is essential for X chromosome inactivation.
Barakat TS, Gunhanlar N, Pardo CG, Achame EM, Ghazvini M, Boers R, Kenter A, Rentmeester E, Grootegoed JA, Gribnau. (2011). PLoS Genet. 2011 Jan 27;7(1):e1002001.

X chromosome inactivation and embryonic stem cells.
Barakat TS, Gribnau J. Adv Exp Med Biol. 2010;695:132-54.

A murine ESC-like state facilitates transgenesis and homologous recombination in human pluripotent stem cells.
Buecker C, Chen HH, Polo JM, Daheron L, Bu L, Barakat TS, Okwieka P, Porter A, Gribnau J, Hochedlinger K, Geijsen N. (2010). Cell Stem Cell. 2010 Jun 4;6(6):535-46.

X-changing information on X inactivation.
Barakat TS1, Jonkers I, Monkhorst K, Gribnau J. (2010). Exp Cell Res. 2010 Mar 10;316(5):679-87.

RNF12 is an X-Encoded dose-dependent activator of X chromosome inactivation.
Jonkers I, Barakat TS, Achame EM, Monkhorst K, Kenter A, Rentmeester E, Grosveld F, Grootegoed JA, Gribnau J. (2009). Cell. 2009 Nov 25;139(5):999-1011.

Books

Living with two X chromosomes: of mice and women : studies on the initiation mechanisms of X chromosome inactivation in stem cells and mouse models, and the role of RNF12 herein

Other publications

X-chromosome inactivation and its implications for human disease.
Joost Gribnau, Tahsin Stefan Barakat.

Can adrenaline safely be used in local anaesthesia involving distal extremities? A systematic review. Tahsin Stefan Barakat, Mariska de Pagter and Michel ten Have. (2015). Erasmus Journal of Medicine 4(2):15-19.