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DR MARIA CHRISTOPHOROU

Genome Regulation

IGMM Chancellor's Fellowship

Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society

 

 

 


DR MARIA CHRISTOPHOROU

Contact Details

E-mail address: Maria.Christophorou@igmm.ed.ac.uk
Telephone: +44 (0)131 651 8617
Fax: +44 (0)131 651 8800
Address: MRC Human Genetics Unit MRC IGMM, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU

 

 

Biography

I obtained a B.Sc. in Biology from MIT as a Fulbright Scholar. During that time, I undertook a two-year UROP (Undergraduate Research Opportunity Program) project at the Whitehead Institute, in the laboratory of Prof. Hazel Sive and under the supervision of Dr. Mary Ellen Lane. This entailed cloning and characterizion of cDNAs involved in the formation of posterior structures of the zebrafish nervous system. In addition, I worked on a number of projects at the Cyprus Institute of Neurology and Genetics (CING), under the supervision of Professor Marios Cariolou.

 

My doctoral work was undertaken at UCSF, in the Biomedical Sciences (BMS) Program, under a UC Regents Doctoral Fellowship. This exposed me to research in different disease-related fields and involved rigorous training in histopathology and organismal biology. I completed my doctoral dissertation in the laboratory of Prof. Gerard Evan, at the UCSF Comprehensive Cancer Center. Using mouse models and cell culture systems of conditional p53 perturbation, I was able to dissect the relative contributions of different p53 activating signals towards tumour suppression.

 

In order to expand my expertise into basic biochemistry and molecular biology, I joined the laboratory of Prof. Tony Kouzarides at the Gurdon Institute, University of Cambridge. My work there was funded by Long-Term Postdoctoral Fellowships from EMBO and HFSP and focused on chromatin modifying enzymes and the mechanisms through which they modulate cell function. Specifically, I uncovered a new role for the peptidylarginine deiminase PADI4 in the regulation of pluripotency and described a molecular mechanism by which it mediates chromatin decondensation, through citrullination of the linker histone H1.

 

In 2014 I was awarded a Chancellor’s fellowship from the University of Edinburgh and a Sir Henry Dale fellowship form the Wellcome Trust and Royal Society to establish an independent research group at the MRC Institute of Genetics and Molecular Medicine.

 

Academic qualifications

Bachelor of Science
1999, Biology, MIT

 

Doctor of Philosophy
2005, Biomedical Science, UCSF

 

Research in a Nutshell

The number of protein-coding genes in the genome does not nearly account for the number of processes necessary for an organism’s vital functions. Small chemical changes, called post-translational modifications (PTMs), are made on proteins by enzymes and determine when, where and how proteins work. As such, PTMs fine-tune protein function and add an enormous degree of sophistication to biological systems.  By the same token, abnormal deposition of PTMs by malfunctioning modifying enzymes can deregulate proteins and upset normal cellular function in the same way that a mutation in a critical gene would. Importantly, the modifying enzymes lend themselves to modulation by externally added compounds (such as specific chemical inhibitors) and therefore understanding the way they work presents exciting possibilities for therapeutic intervention.

 

The PTM citrullination (or deimination) is the conversion of an arginine residue to the non-coded amino acid citrulline. It is carried out by enzymes called peptidylarginine deiminases (PADIs) and can modulate a protein's function by altering its structure, changing its sub-cellular localisation and affecting its interactions with other molecules. Our recent work has shown that citrullination regulates pluripotency, the ability to generate any type of cell from a stem cell, which holds great promise for regenerative medicine. Notably, abnormal citrullination is a pathological feature of diseases such as autoimmunity (rheumatoid arthritis, multiple sclerosis, ulcerative colitis, psoriasis), neurodegeneration (Alzheimer's and prion diseases), atherosclerosis and cancer. In certain cases it serves as a marker of diagnostic and prognostic value, while its inhibition has shown early promise in disease-based experimental systems. Despite the likely mechanistic importance of citrullination in both cell physiology and disease, it remains largely unexplored.

 

The central aims of our work are to define how PADIs are regulated and understand how their deregulation contributes to disease development. We employ a combination of biochemical, molecular and cell biological approaches, as well as in vivo model systems. We hope that this work will significantly advance our current understanding of citrullination and explore new regulatory mechanisms involved in both physiology and disease.