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Edith Heard from the Institut Curie in Paris talks about her research into the epigenetics of X chromosome inactivation.
Although I was good at science at school, I was not sure I wanted to become a scientist initially (I loved history and music…).
I only really decided to pursue a career as a research scientist at the very end my undergraduate studies, when I specialized in genetics at Cambridge University. Having come from a more mathematical or physics background, I felt I was a bit of a slow starter and I was therefore quite reluctant to launch into a PhD, given how little experience I felt I had in biology.
However, I was really encouraged by some (though not all!) of my supervisors at the time and I realized that I was very interested in getting to the bottom of questions. So I decided to give a PhD a go at the Imperial Cancer Research Fund – I felt that if I was to be a scientist, I might as well try to be useful by studying cancer.
Although my project was quite challenging (working on gene amplification in cancer cells), I was in an incredibly stimulating environment and I gradually realized that this was indeed probably the career for me.
I have to admit I had not really heard of X inactivation until my PhD! It was while reading about the possible roles of DNA methylation in mammalian cells that I first stumbled across X inactivation. Robin Holliday had written a rather inspiring review on the potential implication of epigenetics in cancer as well as in normal processes such as X inactivation.
As my PhD drew to an end, I realized that to understand how gene regulation can go wrong in cancer cells, one first had to understand how it occurs during normal development, so I decided that I wanted to work on a developmental process, such as X-chromosome inactivation.
I was advised to apply to either Hunt Willard's lab in the USA or Phil Avner's lab in France at the Pasteur Institute – and as my partner happened to be French, I chose the latter option. My project was initially about the genetic control of X inactivation: hard core physical mapping, as well as transgenesis to define the key region (the X-inactivation centre) that controls the process. It was a lot of molecular biology, and handling large DNA molecules…
As time passed, I got more and more interested in the epigenetics of X inactivation. I spent a year at Cold Spring Harbor in David Spector's lab to explore the role of nuclear organization in this process and while I was there I bumped into Dave Allis, who really launched me into the exploration of chromatin changes involved in X-chromosome silencing.
My team was one of the first to show that the early stages of X inactivation involve nuclear reorganization of the X chromosome. The non-coding X inactive specific transcript (Xist) RNA coats the chromosome in cis, creates what appears to be a silent compartment into which genes are relocated, and induces changes both in the chromatin state and 3D organization of the chromosome.
Our recent work is starting to shed some light on the changes in X-chromosome structure and how these are related to gene activity states. Following on from the discovery of topologically associating domains at the X inactivation centre (Xic) locus by Elphège Nora in my lab (in collaboration with Job Dekker's lab), we have gone on to explore the overall organization of the inactive X chromosome, both at the level of genes that are silenced as well as those that escape.
We now want to understand how exactly gene regulation relates to these changes in 3D organization and to chromatin structure. What are the first events in gene silencing during X inactivation: are they at the level of the promoter or enhancers? Do they involve chromatin regulators, or specific repressor transcription factors? Our ongoing efforts are to identify the precise role of chromatin changes and chromosome organization in gene silencing and escape.
Many! How is initial mono allelic regulation of X inactivation ensured? How does Xist RNA trigger chromosome-wide silencing? How do genes actually become silenced – are there many modes of silencing (not all genes are silenced simultaneously), and how do some genes manage to avoid this process altogether? What constitutes the epigenetic memory of the inactive X?
We still have a lot to understand about the nature of the chromatin changes that ensure the incredible stability of the inactive state, and how these can be reversed during reprogramming in the germ line. Also, we want to know more about the epigenetic instability of the inactive X chromosome in cancer.
Most data points or results that don't fit with what we were expecting end up pointing to the next discovery – in my experience! That is why I am a firm believer of reporting such unexpected results – and also negative results – in publications if possible: they leave the open door to the field!
Our observation that in early mouse embryos, the X chromosome is first silenced, then transiently reactivated in the inner cell mass of the blastocyst (reported in Okamoto et al., 2004) was one of those moments, as was our work in human embryos showing that both X chromosomes are coated by Xist RNA, but not silenced until much later.
Our work on the Xic has been an example of several such “Eureka!” moments. For example, after decades of trying to use transgenesis to determine the extent of this region, and failing – single copy transgenes of even 500 kb could not recapitulate Xic function – our recent work using 5C led to the discovery of topology associating domains (TADs, see Nora et al., 2012).
This work demonstrated that the Xic must consist of at least two TADs, together spanning almost 800 kb. The moment when we first saw this TAD organization of the Xic was really exciting – we were initially perplexed, but then realized that this might finally explain why we had not been able to define the single copy Xic so far! And it pointed us to tons of the missing elements.
First, choose an important question (and don't get distracted with other smaller questions along the way, however trendy they may seem). Then keep an open mind about any results that your experiments give you…
Second, have extreme concentration and perseverance – two critical hallmarks of any successful research scientist in my opinion!
Third, be humble and generous, and propagate knowledge and tools so science can move forward and the younger generation can go further!
I would be tempted by neurobiology – I feel that there are some incredible tools out there now and I think we are all fascinated by how the brain works. I would be really interested to understand what the role of chromatin is in gene regulation during neuronal development and also during aging.
Having said that there is still so much to learn about X inactivation, and it opens up new questions all the time that touch on so many different topics (chromosome structure, gene dosage, chromatin, RNA, development, disease…).
Also I feel that it is much easier to be inter-disciplinary now in biology; many of my lab members and collaborators are physicists for example. This has only happened in recent years and is very exciting as one feels that we may be getting closer to understanding the fundamental principles of processes such as chromatin folding.
My family: my partner and my two children!