From whales to earthworms, the mechanism that gives shape to life
14.10.11 - Mice don’t have tails on their backs, and their ribs don’t grow from lumbar vertebrae. And for a good reason. EPFL scientists have discovered the mechanism that determines the shape that many animals take – including humans, blue whales, and insects.
Why don’t our arms grow from the middle of our bodies? The question isn’t as trivial as it appears. Vertebrae, limbs, ribs, tailbone ... in only two days, all these elements take their place in the embryo, in the right spot and with the precision of a Swiss watch. Intrigued by the extraordinary reliability of this mechanism, biologists have long wondered how it works. Now, researchers at EPFL (Ecole Polytechnique Fédérale de Lausanne) and the University of Geneva (Unige) have solved the mystery. Their discovery will be published October 13, 2011 in the journal Science.
The embryo is built one layer at a time
During the development of an embryo, everything happens at a specific moment. In about 48 hours, it will grow from the top to the bottom, one slice at a time – scientists call this the embryo’s segmentation. “We’re made up of thirty-odd horizontal slices,” explains Denis Duboule, a professor at EPFL and Unige. “These slices correspond more or less to the number of vertebrae we have.”
Every hour and a half, a new segment is built. The genes corresponding to the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae and the tailbone become activated at exactly the right moment one after another. “If the timing is not followed to the letter, you’ll end up with ribs coming off your lumbar vertebrae,” jokes Duboule. How do the genes know how to launch themselves into action in such a perfectly synchronized manner? “We assumed that the DNA played the role of a kind of clock. But we didn’t understand how.”
When DNA acts like a mechanical clock
Very specific genes, known as “Hox,” are involved in this process. Responsible for the formation of limbs and the spinal column, they have a remarkable characteristic. “Hox genes are situated one exactly after the other on the DNA strand, in four groups. First the neck, then the thorax, then the lumbar, and so on,” explains Duboule. “This unique arrangement inevitably had to play a role.”
The process is astonishingly simple. In the embryo’s first moments, the Hox genes are dormant, packaged like a spool of wound yarn on the DNA. When the time is right, the strand begins to unwind. When the embryo begins to form the upper levels, the genes encoding the formation of cervical vertebrae come off the spool and become activated. Then it is the thoracic vertebrae’s turn, and so on down to the tailbone. The DNA strand acts a bit like an old-fashioned computer punchcard, delivering specific instructions as it progressively goes through the machine.
“A new gene comes out of the spool every ninety minutes, which corresponds to the time needed for a new layer of the embryo to be built,” explains Duboule. “It takes two days for the strand to completely unwind; this is the same time that’s needed for all the layers of the embryo to be completed.” This system is the first “mechanical” clock ever discovered in genetics. And it explains why the system is so remarkably precise.
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Read more here/Leia mais aqui: EPFL
Read more here/Leia mais aqui: EPFL
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Science 14 October 2011:
Vol. 334 no. 6053 pp. 222-225
DOI: 10.1126/science.1207194
REPORT
The Dynamic Architecture of Hox Gene Clusters
Daan Noordermeer1, Marion Leleu1, Erik Splinter2, Jacques Rougemont1,3, Wouter De Laat2, Denis Duboule1,4,*
Author Affiliations
1National Research Centre “Frontiers in Genetics,” School of Life Sciences, Ecole Polytechnique Fédérale (EPFL), Lausanne, CH-1015, Switzerland.
2Hubrecht Institute and University Medical Center, Utrecht, 3584 CT, Netherlands.
3Swiss Institute of Bioinformatics, Lausanne, CH-1015, Switzerland.
4Department of Genetics and Evolution, University of Geneva, CH-1211, Switzerland.
*To whom correspondence should be addressed. E-mail: denis.duboule@unige.ch or denis.duboule@epfl.ch
ABSTRACT
The spatial and temporal control of Hox gene transcription is essential for patterning the vertebrate body axis. Although this process involves changes in histone posttranslational modifications, the existence of particular three-dimensional (3D) architectures remained to be assessed in vivo. Using high-resolution chromatin conformation capture methodology, we examined the spatial configuration of Hox clusters in embryonic mouse tissues where different Hox genes are active. When the cluster is transcriptionally inactive, Hox genes associate into a single 3D structure delimited from flanking regions. Once transcription starts, Hox clusters switch to a bimodal 3D organization where newly activated genes progressively cluster into a transcriptionally active compartment. This transition in spatial configurations coincides with the dynamics of chromatin marks, which label the progression of the gene clusters from a negative to a positive transcription status. This spatial compartmentalization may be key to process the colinear activation of these compact gene clusters.
Received for publication 19 April 2011.
Accepted for publication 17 August 2011.
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