A liver cell is not a muscle cell, and yet they share the same DNA. Behind this difference are sequences regulating gene expression, which Salvatore Spicuglia has been studying for almost twenty years. An endeavor honored by the Bettencourt-Schueller Foundation Coups d’Élan Prize for French Research.
"In his book, The Statue Within, François Jacob, winner of the 1965 Nobel Prize in Medicine, wrote that research often comprises unexpected findings and that it is especially the atypical minds which have the capacity to seize them", concluded Salvatore Spicuglia from the Theories and Approaches of Genomic Complexity* laboratory in Marseille, in the wake of being awarded the Bettencourt-Schueller Foundation Coups d’Élan Prize for French Research. Words that apply to his career in which open-mindedness and fate have counted for a lot.
Originally from Venezuela, Spicuglia, who was still a high school student in the early 1990s, obtained a scholarship to study abroad. "I was already interested in genetics and had picked out an engineering school in Strasbourg. So I chose to go to France", he recalls. Although he did not enroll there in the end, he did not abandon genetics. As part of his scholarship, he retook his baccalaureate in Montpellier and learned French. Next step was a Biology DEUG – equivalent to the first two years of a bachelor’s degree today – in Lille and a Cellular and Molecular Biology senior diploma in Lyon. "We had a class on genetic stability, and more particularly on DNA rearrangements in lymphocytes, he explained. The subject immediately piqued my interest, so I asked the tutor where I might study it further. She pointed me in the direction of Pierre Ferrier** at the Center of Immunology Marseille-Luminy (CIML)." Senior diploma obtained, Spicuglia headed to Marseille where he completed a Masters in 1998 and a Ph.D. in 2002.
Since then, he has continued to explore the field of epigenetics, "namely, the regulation of genes which, in an organism, ensures that skin cells do not resemble nerve cells, even though they share the same genetic heritage, he explains. These cells therefore read the same DNA differently. This reading is done by regulatory sequences – like orchestra conductors – of which there are two types. Promoters, which are located just next to the genes, and enhancers, which control gene expression remotely by acting on their promoters." During his Ph.D., Spicuglia identified and studied in mice those which control the expression and the rearrangement of the genes coding for the receptors of the T-cells that enable these cells to recognize antigens.
Towards the end of his Ph.D., the sequencing of the human genome had just been completed. "And several laboratories worldwide were developing high-throughput sequencing approaches making it possible to study epigenetic regulation mechanisms on the scale of the genome, he remembers. So I opted to do my post-doctoral fellowship at Nijmegen University in the Netherlands, in the laboratory of Henk Stunnenberg, an epigenetics specialist and pioneer of these approaches." After two and a half very rewarding years,
Spicuglia returned to his former laboratory in Marseille where he took up the role of Inserm Research Officer. He implemented these new high-throughput tools in order to study mechanisms of epigenetic regulation during T-cell differentiation in humans and mice. "With this we identified particular modifications in the organization of the histones that are located in the regulatory elements of the genome, he explains. And although back then these ‘histone profiles’ were deemed anecdotal by part of the scientific community, they are now considered key components of epigenetic regulation. Proof of this was when the European consortium Blueprint , of which I am a member, published in 2016 the various ‘histone profiles’ identified in human hematopoietic cells. And then at the end of the year there will be the launch of Enhpathy, a European consortium that I am coordinating, which aims to train young researchers in the study of impaired enhancers in diseases."
- 2002. Prize for best Ph.D. thesis, Université d’Aix-Marseille II
- 2003-2005. Post-doctoral fellowship at Nijmegen University, Netherlands
- 2005. Inserm Research Officer
- 2011. Authorization to supervise research
- Since 2011. Functional genomics of T cell differentiation and leukemia group leader at the Theories and approaches of genomic complexity laboratory in Marseille
In 2011, the researcher took his independence and created his own team. "I chose to join my current laboratory because I considered its bioinformatics expertise essential for analyzing the data obtained with the new genomics tools", he indicates. There he continues to study the regulatory elements in T-cells. However, as he emphasizes, "finding promoters is simple because they are just upstream of the genes, but for amplifiers it is complicated. They can be anywhere on the genome – very remote from or upstream or downstream of the genes whose expression they regulate". To detect them, the researcher uses epigenetic histone marks, but "it is about correlation. Meaning that there where there are these marks, the DNA sequence is likely to be an enhancer. Then we have to ascertain whether or not there is indeed this activity, he states. That is why in 2015 we developed a strategy to evaluate the activity of thousands – if not hundreds of thousands – of sequences simultaneously."
And it was then that the team discovered – "by chance", emphasizes Spicuglia – the e-promoters that earned it the Bettencourt-Schueller Foundation prize. "To evaluate our approach of high-throughput identification of potential enhancer sequences, we used – in parallel – promoters, which are not meant to act on genes located remotely, he explains. However, against all expectations, many of them turned out to have an amplifying action. We thought it was a handling error at first. But the results remained the same, despite repeating the experiment several times and after changing various parameters. It could no longer be denied that some promoters do indeed act in a similar way to the enhancers." In the wake of this finding, the researchers tested all the promoters of the genome in order to identify those with this dual function.
The impact of this research on epigenetics is far from being fully determined. "Until recently, we were mostly interested in gene mutations, but that is only the tip of the iceberg. E-promoter or enhancer abnormalities certainly affect many genes and are no doubt responsible for a variety of diseases, assures Spicuglia. It has recently been shown, in prostate cancer, that a mutation in a promoter confers it an amplifying action on oncogenes located remotely."
At present, the aim of the laboratory is therefore to understand how mutations in the regulatory parts of the genome influence disease development and progression, particularly in leukemia and inflammatory diseases. A task of monumental proportions facilitated by the 250,000 euros accompanying the Bettencourt-Schueller Foundation prize, which will enable the laboratory to buy new equipment.
*unit 1090 Inserm/Aix-Marseille Université
**unit 1104 Inserm/CNRS/Aix-Marseille Université