The double-helix 70 years on: five FMI studies that helped decipher the DNA

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 (Immagine: Pixabay CC0)
(Immagine: Pixabay CC0)

On April 25 by James Watson and Francis Crick. Their study revolutionized the field of molecular biology and laid the foundation for modern genetics and genomics. Seventy years later, there remains a lot to discover about the "molecule of life" and scientists at the FMI are at the forefront of such research. The anniversary celebrated today is a good opportunity to look at some key FMI studies that have advanced our understanding of DNA.

It is a common misconception that Watson and Crick have discovered DNA. While their description of the structure of DNA undoubtedly was one of the greatest biomedical discoveries of the 20th century, it was Basel-born biochemist Friedrich Miescher who discovered DNA. In 1869, Miescher isolated a substance from the nuclei of white blood cells and named it "nuclein". However, he did not know that nuclein, which was later renamed DNA, was the carrier of genetic information in all living organisms.

When the FMI was established in 1970, its founders named it after Friedrich Miescher to celebrate the discovery of DNA a century earlier and because they wanted DNA to be a central focus of the institute’s research. Over the years, the FMI has made key contributions to our understanding of DNA. To this day, its scientists are dedicated to deciphering the role played by our genes in health and disease.

To illustrate the past and present breadth of our DNA research, we selected five studies — among many others — by FMI scientists that helped to elucidate the structure and function of DNA.

Protocols for plant transgenesis
In 1976, the FMI set out to conduct research in molecular plant biology, a discipline that hardly existed before the early 1970s. The institute soon became a leader in plant transgenesis — a technique to introduce foreign genetic material into plant cells, ushering in the era of genetically improved crops. In 1984, several FMI groups published two protocols that allowed foreign genes to be expressed in whole plants. These methods were more robust and straightforward than previous approaches. In the following years, FMI researchers further optimized the methods and patented several of their findings. In 2000, the FMI discontinued research in plant science and shifted its focus to epigenetics.

Original publication :
Jerzy Paszkowski, Raymond D. Shillito, Michael Saul, Václáv Mandák, Thomas Hohn, Barbara Hohn, Ingo Potrykus. Direct gene transfer to plants The EMBO Journal (1984) 3:2717-2722

Mapping DNA methylation
Epigenetic modifications such as DNA methylation play an important role in gene regulation by controlling gene activity without changing the DNA sequence. Since early research in DNA methylation in the 1980s, the FMI has been recognized as a leader in epigenetics. In 2005, the institute’s researchers devised a new method to map epigenetic modifications across the genome, which allowed them to produce the first genomic maps of DNA methylation. The method became a common diagnostic tool. The FMI findings contributed to the emerging field of epigenomics — the comprehensive study of epigenetic changes.

Original publication :
Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL, Schübeler D. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. (2005) 37(8):853-62

How small RNAs control gene expression
In the early 2000s, microRNAs (miRNAs) — small RNA molecules involved in the regulation of gene expression — were recognized as biological regulators that held promise for the diagnosis and treatment of human disease. In 2005, FMI researchers discovered that miRNAs repress gene expression in human cells by inhibiting protein synthesis at an early step of the process. FMI scientists were also among the first to show the importance of cytosolic membrane-less structures called P-bodies in the function of miRNAs. The FMI has maintained a leading role in the field of RNA biology, with several groups studying how RNA controls gene expression.

Original publication :
Ramesh S Pillai, Suvendra N Bhattacharyya, Caroline G Artus, Tabea Zoller, Nicolas Cougot, Eugenia Basyuk, Edouard Bertrand, Witold Filipowicz. Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science (2005) 309(5740):1573-6

How DNA damage is repaired
Structural analysis of DNA is an important tool for understanding the physical and chemical properties of this important molecule and can be critical to develop new medicines. Using structural biology approaches, FMI scientists have made key contributions to our understanding of DNA repair — a process that is essential for safeguarding the genome and preventing mutations that can lead to diseases such as cancer. In 2008, FMI researchers provided the structure of a protein complex called DDB1-DDB2 bound to DNA. The complex plays a crucial role in nucleotide excision repair, one of the pathways used by the cell for repairing damaged DNA after ultraviolet-induced damage. Further studies using a revolutionary technology called cryo-electron microscopy allowed researchers to understand how exactly repair protein — and most likely many other types of proteins — access the DNA molecule.

Original publication :
Andrea Scrima, Renata Konícková, Bryan K Czyzewski, Yusuke Kawasaki, Philip D Jeffrey, Regina Groisman, Yoshihiro Nakatani, Shigenori Iwai, Nikola P Pavletich, Nicolas H Thomä. Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex. Cell (2008) 135(7):1213-23

The role of chromatin organization in genome stability
Eukaryotic genomes contain millions of copies of repetitive elements, which are invasive with no role at all. Most are kept "silent" by the posttranslational modification of histones, which allows repetitive DNA to be packaged into an inactive form of chromatin. This so-called heterochromatin is stabilized across all species by dior tri-methylation of lysine 9 in the core histone H3. In a study using the nematode C. elegans, FMI researchers hindered the methylation to occur. As a result, most heterochromatin in the worm nuclei shifted away from its usual peripheral compartment, and repetitive DNA was transcribed. The resulting worms could develop, but became sterile and short-lived. This reflects the death of germ cells, which accumulated very high levels of DNA damage at repetitive sequences. Later studies showed that the loss of transcriptional repression is lethal when combined with mutations in the breast cancer genes BRCA1 or BRCA2 that contribute to the repair of DNA damage.

Original publication :
Peter Zeller, Jan Padeken, Robin van Schendel, Véronique Kalck, Martin Tijsterman, and Susan M. Gasser. Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability. Nature Genetics (2016) 48(11):1385-1395