Scientist of the month: Tony Kouzarides

So far 2014 has seen the Kouzarides lab describe a new histone modification, methylation of glutamine, on H2A (Tessarz et al, 2014) ; highlight a new role for citrullination in the regulation of pluripotency (Christophorou et al, 2014) and suggest a pathway that underlies the role of EMSY in breast cancer (Viré et al, 2014). Abcam caught up with Tony in his lab at the Gurdon Institute, to find out more about his research interests and thoughts on Epigenetics.

Brief biography

Tony Kouzarides PhD

Tony Kouzarides completed his PhD at the University of Cambridge and postdoctoral work at the MRC laboratory of Molecular Biology on the cancer inducing potential of human cytomegalovirus. He then moved to NYU Medical Center in New York where he defined the functions of the c-Fox leucine zipper dimerisation domain. In 1991, Tony moved back to Cambridge where he's lead a research group at the Gurdon Institute ever since.

Tony is the founder and director of the charity "Vencer el Cancer" (Conquer Cancer), based in Spain, which raises public funds for cancer research and drug discovery. He is a founder of Chroma therapeutics, a UK based cancer drug discovery company, which has at its focus enzymes that modify chromatin. He is also a co-founder of Abcam plc.

Amongst many accolades he was elected member of the European Molecular Biology Organization, the British Academy of Medical Sciences and the Royal Society. He has been awarded Novartis medal and prize, the Wellcome Trust medal for research in biochemistry related to medicine, the Tenovus Medal, the Bodosski Foundation prize in Biology, the Bijvoet Medal and the Heinrich Wieland medal and prize. At the time of writing this, he has authored over 160 papers.

Q. Briefly what are your labs current research interests?

Our current interests involve the identification and characterization of new classes of enzymes that modify chromatin. Our focus is on understanding the biological out-put of these new modifications, but also understanding their connection to cancer. Our experience so far has been that the discovery of new classes of modification lead to the discovery of new pathways associated with cancer.

We believe that there are many other modifications to be uncovered so we are continuing on this path. We are also collaborating with pharmaceutical companies to identify small molecule inhibitors of these pathways. Our optimism on the effectiveness of small molecules in disrupting epigenetic pathways comes from our collaboration with GSK on the BET protein inhibitor iBET. In a couple of years, we and our collaborators showed that disrupting the binding of these acetyl-readers to chromatin could be effective against MLL-leukemia (Dawson et al, 2011). Based on this data iBET is now in clinical trials here in Cambridge.

We are also interested in non-coding RNAs and their function. In particular we are investigating enzymes that modify RNAs, following our discovery of an enzyme that modifies the 5' phosphate of micro-RNAs (Xhemalce et al, 2012). We found that this was an enzyme that was implicated in cancer, so we believe that other enzymes that modify RNAs could be clinically relevant.

Q. What is the most exciting recent development in your lab?

Most recently we have identified and characterized two new histone modification pathways that are implicated in transcription. The first is a pathway that involves citrullination of proteins, which is the conversion of arginine to citrulline. We defined this modification as one that regulates transcription some years ago. Now we can show that the citrullinating enzyme PADI4 is able to regulate pluripotency by allowing decondensation of chromatin through the removal of histone H1 from condensed chromatin.

The second pathway we have identified is a new class of enzymatic activity, which involves the methylation of glutamine. We identified a novel enzyme in yeast (NOP1) that can methylate histone H2A glutamine 105. This modification regulates the transcription of ribosomal DNA genes by preventing the binding of the FACT complex. As we normally do with the discovery of new pathways in yeast, we tried to see if a similar mechanism occurs in mammalian cells. We have found the Fibrillarin in mammalian cells mediates glutamine methylation in humans and is localized exclusively to sites of ribosomal DNA transcription. So this new class of modification, glutamine methylation, is the first modification to be dedicated to a single RNA polymerase, namely RNA Polymerase I.

Q. What other discoveries and next steps does your research project have in store for us?

We are most excited about the identification of new enzymes of modified RNAs. We have a program to identify these enzymes and have been successful in identifying a number of these. We are now characterizing their substrates and their function.

Q. Which key epigenetic questions would you like to see answered in the next 5-10 years?

One of the major questions to be addressed is that of transgenerational inheritance of modification. This is a very interesting but controversial area of research. It is a difficult but important area to be explored because of its implications with respect to environmental effects over our genetic makeup.

Q. Who were your role models, living or dead, at the start of your career and now?

I would say Curie because of her dedication to science. I would to be as good as her, but would prefer that my science did not have the same effect on my health!

Q. What made you focus on epigenetics research?

Our interest in epigenetics started very early, when we discovered one of the first enzymes that modify chromatin. This was the CBP acetyltransferase in 1996. In this year the first cohort of enzymes that modify chromatin were identified and shown that they were involved in transcription. This led to an assumption that transcription regulation would have to be intimately linked to the process of chromatin regulation. Therefore, we continued to identify new pathways and new modifications of chromatin on the understanding that there will be regulating fundamental biological processes. As it worked out they're also involved in cancer. Soon after we CBP/p300 was an enzyme, we showed that it was deleted in many cancers. This then convinced us that the connection to cancer is an important one that should be pursued.

Q. Any words of wisdom for young researchers just starting?

The wisdom that I hold for myself, and one that I think should be guiding most researchers, is the importance of the question. How transformational is the issue being addressed? Is the outcome of the experimental program going to change the field or just add incremental knowledge?

Q. What would you be working on if you weren't an epigeneticist?

I would be an archeologist. Archeology is something I've always been interested in but did not pursue academically. As it happens, biological research is very similar: we are trying to discover things that nobody knows about!

Q. One thing you could not live without? (inside or outside the lab)

My family and friends.


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