... / ... / ... / Principal Investigators / Stefan Barakat, MD, PhD

Stefan Barakat, MD, PhD

Dr. Stefan Barakat, M.D., PhD, MSc Stefan Barakat
Principal investigator

Department of Clinical Genetics
Erasmus MC
Faculty Building, Ee930/Ee2081
Wytemaweg 80

3015 CN Rotterdam 

The Netherlands   

Email: t.barakat@erasmusmc.nl
Tel: +31 (0) 10 7030051
 



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. Despite the fact that we know that the majority of DNA sequences (~98%)  in the human genome do not encode protein-coding genes, our understanding of those sequences and why they are important is still far from complete. An important group of non-coding genome elements are enhancers that are crucial for the proper regulation of spatiotemporal gene expression. Despite the fact that several techniques (e.g. ChIP-seq, chromatin accessibility assays etc.) can predict the identity of enhancers, it is still very challenging to predict the activity of these sequences. During my postdoctoral training, I have developed a new approach which combines chromatin immunoprecipitation with a massively parallel reporter assay that allows generation of comprehensive, genome-wide enhancer activity maps for various cell types. This work has generated one of the largest resources of functionally validated enhancers in human embryonic stem cells existing to date (available at http://hesc-enhancers.computational-epigenetics.org), which will enable further knowledge-based studies to decipher the code underlying the regulation of genes by non-coding sequences. Using these data, we discovered that only a small fraction of genomic regions bound by transcription factors or marked by histone modifications generally believed to be correlated to enhancers, do show measurable enhancer activity in human embryonic stem cells. Active sites show a distinct protein binding profile and enrichment for sequences derived from transposable elements. Enhancer activity changes dramatically upon developmental transitions during differentiation, and only small constituents of “super-enhancers” are responsible for enhancer activity.  
 
We are now using similar techniques and various other approaches, including induced pluripotent stem cells and cerebral organoids (“mini-brains”), to study the enhancer landscape in cells representing neurodevelopment. As many genetic disorders of brain development can at present not be explained by routine genetic diagnostics, we anticipate that many of these disorders are caused by alterations of non-coding elements, including enhancers. We plan to sequence the enhancers identified through our genome-wide functional enhancer activity assays in patients, to directly test the hypothesis that alterations of non-coding genome regions can be causal in the pathogenesis of brain disorders. We can then apply disease modelling for the patients harboring identified mutations, using patient specific induced pluripotent stem cells and differentiation to cerebral organoids, thereby simulating brain development in a dish. Our studies will facilitate the identification of functional enhancer sequences in the non-coding genome, and will allow novel innovative approaches for patient diagnostics using functional genomics.


Curriculum Vitae

2017-present  Resident in Clinical Genetics (AIOS), Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

2017-present  Research Group leader, Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

2015 – 2017  Postdoctoral Fellow, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom. Lab of prof. dr. Ian Chambers

1/1/2013-28/11/2014  Clinical Training (“co-schappen”) to obtain degree of Medical Doctor (Physician), Erasmus MC, University Medical Center, Rotterdam, The Netherlands

13/09/2012 – 31/12/2012  Postdoctoral Fellow (awaiting start of Clinical Training), Department of Reproduction and Development, Erasmus MC- University Medical Center, Rotterdam, The Netherlands. Lab of prof. dr. Joost Gribnau

01/09/2008 – 12/09/2012  PhD Student, Department of Reproduction and Development, Erasmus MC- University Medical Center, Rotterdam, The Netherlands. Supervisors: prof. dr. Joost Gribnau and prof. dr. J.Anton Grootegoed

01/09/2004–31/08/2008  Master of Science in Molecular Medicine, Faculty of Medicine and Health Science, Erasmus MC- University Medical Center, Erasmus University Rotterdam, The Netherlands

01/09/2003-15/11/2007  Medicine, ‘doctoraal’ (cum laude), Faculty of Medicine and Health Science, Erasmus MC- University Medical Center, Erasmus University Rotterdam, The Netherlands