Mira Kassouf

I am an RDM PI in the Laboratory of Gene Regulation at the MRC Weatherall Institute of Molecular Medicine, University of Oxford. I study how genes are switched on and off in development, differentiation and disease, with a focus on the non-coding DNA.

While we have decoded the genetic code that translates DNA to proteins, we lack comparable understanding of the "genomic code"—how non-coding DNA orchestrates when, where, and the level at which genes are expressed. This knowledge gap limits our ability to predict disease outcomes from genetic variants that occur mostly in the non-coding DNA and to design therapeutic interventions.

My research focusses on the non-coding cis-regulatory elements; their sequence, orientation, context and how they relay information to achieve precise gene expression.  

A deeper dive

Mammalian gene expression relies on three fundamental regulatory elements: promoters that initiate transcription, enhancers that activate genes from afar (10s-1000s kb), and insulators that compartmentalise the genome into functional domains. While promoters reside adjacent to genes, enhancers and insulators are scattered throughout the 98% of non-coding DNA. During development and differentiation, these dispersed elements must find each other in three-dimensional nuclear space to activate precise gene expression programs. This gets more complicated How this happens is still unclear.

What initially appeared to be a simple biological problem - an enhancer regulating a nearby gene - has proven remarkably complex. The enhancer-promoter interaction is influenced by many factors. These include enhancer clusters involved in regulating single genes (such as super-enhancers (SEs)), types of enhancer-like elements including 'weak or inactive' enhancers, genomic distances, epigenetic landscape, SE orientation, insulator presence and positions, enhancer-promoter affinity, and 3D chromatin organisation. Further complexity arises from the functional overlap between enhancers, promoters, and insulators.

To navigate through these complexities, I have followed a single-locus study approach. I developed a tractable mammalian system using the mouse red cell-specific gene, the alpha globin locus, as a model mammalian gene whose regulation involves all classes of cis-elements in question. Using cutting-edge genome engineering, synthetic biology, functional genomics and bioinformatics, I plan to dissect and manipulate these sequences as well as the proteins that bind to them and analyse the effect of these perturbations on alpha-globin expression in mouse during erythroid differentiation. Using this well-established system, I have contributed new knowledge to the field of gene regulation over the past 5 years.

I have discovered of a new class of cis-regulatory elements I named "facilitators", sometimes confused for 'weak or inactive' enhancers. Within a SE, facilitators lack intrinsic enhancer activity but are necessary for classical enhancers to fully upregulate their target genes. This finding may have a similar impact to the discovery of enhancers, promoters and insulators on gene regulation and genetic disease. Understanding how these elements function is one of the currently outstanding questions in gene regulation and one of the main questions I address in my lab. I have also challenged the paradigm of enhancer biology that defines enhancers as sequences that drive gene expression from a distance, in an orientation-independent manner. I showed that a SE functions in an orientation-dependent manner. The molecular mechanism underlying this functional polarity is another focus for my research.

Moving forward, I propose to answer more questions by building regulatory domains from scratch using synthetic biology and advanced genome engineering approaches, creating fully controlled experimental systems where every nucleotide can be designed and modified. This approach moves beyond observation to systematic reconstruction, enabling definitive tests of regulatory principles.

Collaborations

The Wellcome Trust SynHG project

An ambitious new research project, SynHG (Synthetic Human Genome), is aiming to develop the foundational and scalable tools, technology and methods needed to synthesise human genomes. Through programmable synthesis of genetic material we will unlock a deeper understanding of life, leading to profound impacts on biotechnology, potentially accelerating the development of safe, targeted, cell-based therapies, and opening entire new fields of research in human health. Achieving reliable genome design and synthesis – i.e. engineering cells to have specific functions – will be a major milestone in modern biology.

The Dark Matter Project

In collaboration with Prof Jef Boeke (NYU Langone Health), we synthesise variants of the mouse α-globin gene to replace the naturally-occurring α-globin gene in mice and mouse cell lines in order to explore their effects on the production of α-globin. This approach will allow us to further our understanding of how gene expression is regulated in general  as well as gain invaluable insight into the underlying causes of α-thalassemia, help develop strategies to correct the disease.

MRC National Mouse Genetics Network Technology Cluster

Along with Prof Ben Davies (The Francis Crick Institute), I am a co-investigator on an MRC grant dedicated to promoting and enhancing use of mouse models for addressing fundamental questions in gene regulation where complex landscapes are involved as well as for modeling human genetic diseases.

Other roles

INNOVATION FORUM OXFORD

I am co-founder and current president of Innovation Forum Oxford, a non-for-profit organisation, part of a global organisation, run by "scientists for scientists" with the mission to inspire, educate, and empower scientific researchers to recognise the value of their research and harness their findings for the benefit of human health. Lowering the barriers for knowledge exchange and collaborations with the outside world (industry, NHS, policy makers, enablers)  is at the heart of the events we design and deliver. This has been acknowledged by the University of Oxford as we were awarded the Knowledge Exchange Seed Fund for our 2018 workshop series (ACE saturdays) and three independent nominations (MRC WIMM, MSD Business Development Office, OUI) for the 2018 Vice-chancellor Inaugural Innovation Award. Interview

WE ACE

With a focus on shining the light on Women Entrepreneurs (WE), I created WE ACE 2020; the programme had a personalised approach to addressing the needs of women at various stages in their early entrepreneurial journey, equipping participants with leadership and negotiation skills. After 4 years of running and more than 70 participants, the programme created a community of trailblazing women entrepreneurs in the health and life sciences.

Oxford University Knowledge Exchange Seed Fund 

I am the chair of the committee for the KE Seed fund. This is an internal grant scheme designed to support Knowledge Exchange activities and projects. It is supported by the University’s Higher Education & Innovation Fund (HEIF) award to ‘support and develop a broad range of knowledge-based interactions between universities and the wider world, which result in economic and social benefit to the UK. ’

RDM Charter Leads Implementation Committee

I amd member of The Charter Implementation Group (Charter Leads) of the Radcliffe Department of Medicine (RDM) responsible for advising on and championing the operationalization of the Career Development Charter for Researchers (the Charter) within RDM. It can make recommendations to the Career Development Committee (CDC) and or Equality and Diversity Inclusion Committee (EDIC) in relation to broader research environment, career and equality issues.

Messages from WIMM women in STEM

Financial Times Article - Patience in the workplace

education

After completing my BSc at the American University of Beirut (AUB), I was awarded Karim Rida Said Foundation (KRSF) scholarships to complete my graduate studies in the UK; an MSc in Human Genetics at Brunel University and a D.Phil at the University of Oxford. 

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