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Joining forces to tackle the ‘Holy Grail’ of the life sciences

14 Apr 2018

An international consortium led by Kikue Tachibana of IMBA and with IMP Scientific Director Jan-Michael Peters and others has secured a prestigious HFSP Program Grant, worth 1.2 million US Dollars. The three-year project aims to understand how mammalian eggs become totipotent after fertilisation.

After a mammalian egg has been fertilised by a sperm, the two cells’ nuclei are initially physically separate before generating a diploid zygote. This rare and elusive cell has the potential to give rise to all cell types of an organism, including extraembryonic tissue – it is totipotent. To achieve this state, the cell’s epigenetic memory has to be erased by removing all the molecular tags and labels that would otherwise restrict its fate. The resulting “ground state” is absolutely unique and makes the zygote stand out, even among stem cells that can form many but not all cell types and are therefore at most pluripotent.

The process of reprogramming to an epigenetic ‘blank state’ is thought to occur at the level of chromatin, the complex structure made of DNA and the proteins that package it. How a zygote is reprogrammed to become totipotent has been one of the ‘holy grails’ of the life sciences. To this day, hardly anything is known about the underlying mechanism, partly due to the extreme sparsity of mammalian zygotes and their transient existence. Besides, sophisticated methods for the analysis of genome regulation have only recently been developed.

A consortium of four labs in Vienna (Austria), Cambridge (USA) and Kyoto (Japan) has now won a Project Grant from the Human Frontier Science Program Organization (HFSPO) to tackle the question of chromatin reprogramming to totipotency. The team is led by Kiku? Tachibana, a Group Leader at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences. It includes Jan-Michael Peters, Scientific Director of the Research Institute of Molecular Pathology (IMP) in Vienna, Mitinori Saitou, Professor at Kyoto University, and MIT-Professor Leonid Mirny. The four scientists propose to overcome the existing limitations by several ground-breaking innovations and by combining the expertise from different disciplines in an unprecedented way.

"Our aim is to understand how chromatin is reprogrammed within hours after a sperm fertilises an egg to generate a totipotent one-cell embryo, special in its ability to produce an entire new organism", explains Kiku? Tachibana. Her lab will combine mechanistic cell biology with single-cell genomics and genetics in mouse zygotes. Leonid Mirny will contribute bioinformatics and in silico modeling based on polymer physics, Mitinori Saitoh will perform pioneering organoid and stem cell work on ovaries and primordial germ cells, and the lab of Jan-Michael Peters will use biochemical reconstitutions and biophysical single-molecule assays. “It is exciting to be part of such an outstanding team of scientists who are using very different approaches to tackle one of the most important and mysterious processes in biology”, comments Jan-Michael Peters.

The Human Frontier Science Program is an international program of research support, implemented by the International Human Frontier Science Program Organization (HFSPO) based in Strasbourg. Its aims are to promote intercontinental collaboration and training in cutting-edge, interdisciplinary research focused on the life sciences. The 31 winning teams of the 2018 competition for the Research Grants went through a rigorous, year-long selection process in a global competition that started with 771 submitted letters of intent. In total, 34 million US dollars will be awarded over the coming three years to support the top four percent of grant applications.

Image Caption (download link below): Kikue Tachibana (IMBA) and Jan-Michael Peters (IMP).

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