Epigenetic editing: not just a one 'hit' wonder

Reza Roozitalab Posted in General News, Publications 13 November 2017

New research published today in Nature Communications

Collaborating authorstop left clockwise, Professor Louise Jones, Adrienne Morgan, Lily Hoa, Professor John G. Gribben, Dr Michael D. Allen, Dr Gabriella Ficz and lead author Dr Emily Saunderson

For the very first time, researchers at BCI have shown that modifying the ‘epigenome’ of a healthy breast cell is not only possible, but precise enough to initiate a chain reaction of events that make the cell abnormal.

The findings of the research, published in Nature Communications, provide insight into the early development of breast cancer, with the potential of aiding earlier cancer diagnosis and development of novel therapeutics through CRISPR-Cas9 based editing.


Breaking new ground

The Detailed Science: Catalytically inactive Cas9 (called dCas9) is fused to DNA methyltransferases (DNMTs), enzymes that catalyse transfer of methyl tags to cytosines in the DNA, generating 5-methylcytosine (5mC).

 The epigenome refers to a menagerie of chemical compounds and tools that regulate the DNA inside our cells – without making changes to the underlying genetic code.

Epigenetic changes are a hallmark of cancer, but up until now, it has not been known whether these changes on their own are sufficient to push healthy cells down the cancer path.

Using cells from the Breast Cancer Now tissue bank and a modified version of the revolutionary CRISPR gene-editing tool, the team were able to manipulate a healthy breast cell to undergo uncontrolled ‘hyperproliferation’ – abnormally rapid cell division which is an early hallmark of tumour initiation.

To do this, they introduced unique ‘methylation’ tags at a specific DNA location to silence ‘tumour suppressor’ proteins that normally act as guardians to protect a cell from cancer. This single epigenetic ‘hit’ further prevented healthy normal cells from entering a state of ‘senescence’ – a natural phenomenon that occurs during ageing, acting as a break to limit the power of a cell to grow and divide.

Lead author Dr Emily Saunderson said:Emily Saunderson

This has been an amazing project to work on as there isn’t really a rule book yet when it comes to epigenetic editing using CRISPR so we’ve been learning as we go. I think a key factor to the success of the project has been the combination of expertise from different groups in and outside of the BCI, it’s been a great experience to be involved with such a collaborative project.


Exceeding expectations

The research also shows that the epigenetic changes are inherited as long as the cell divides, and that the team’s manipulations permanently and negatively affected the biology of a normal breast cell from a healthy individual.

Lead researcher Dr Gabriella Ficz from QMUL’s Barts Cancer Institute said:

It’s surprising that cells from several healthy individuals are so permissive to gaining this epigenetic change and that one ‘hit’ from an epigenetic editing tool is sufficient to set off this chain reaction of epigenetic inheritance and establish a cancer cell-like gene expression signature.


How can we take advantage of this new tool?

The findings may help scientists to better understand the earliest epigenetic changes which can initiate abnormal cell processes, and the transition between the pre-disease state and cancer.

This could help with the development of new biomarkers for earlier diagnosis.

In the future, epigenetic editing could also be used to design novel therapies by initiating permanent changes to cell biology. This may be a more viable or alternative way forward for gene editing as any potential mistakes would be less damaging than directly editing the DNA sequence, and epigenetic editing would be more easily reversible if needed.

Dr Ficz also explains that the findings could have an impact on our knowledge of ageing and cancer, saying:

Epigenetic fluctuations happen all the time in our cells. We know that, during ageing, our epigenome is progressively distorted - so called ‘epigenetic drift’. It will therefore be exciting to find out if this drift is responsible for initiating or accelerating ageing-associated diseases. Age is the biggest risk in cancer so our work highlights the importance of understanding the mechanism behind epigenetic drift.


 QMUL Epigenetics hub

The QMUL Epigenetics hub was formed to promote interactions amongst the different research groups within Queen Mary University of London that investigate the role of epigenetic mechanisms in basic biological processes and disease pathogenesis.epigenetic hub

In addition, we aim to raise the profile of our work within QMUL and externally in the form of regular inter-lab meetings, public communication, and outreach activities.


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