The next level of gene regulation

Some genes are involved in the development of the fetus. However, studies have shown that the same genes control different body parts, e.g. digits and genitals. Furthermore, these genes are also regulated in the same way, which makes it even harder to know how the same genes give rise to two distinct types of organs. In a breakthrough study published in Science, EPFL and University of Geneva scientists have shown that a family of developmental genes called the “Hox genes” are regulated by a nearby, long DNA sequence. This sequence loops around and covers the Hox genes, allowing only certain genes to be active at a time.

One of the greatest revelations that came from mapping the human genome in 2001 was that, despite our body’s complexity, we actually don’t have many more genes than simpler animals like worms. The reason is that, in mammals, genes are used and re-used many times for different purposes. This phenomenon is particularly true for genes that regulate the development of a fetus, such as the family of Hox genes. These are a group of 39 related genes that produce the complete blueprint, or body plan, of an animal by regulating the placement of segment structures in early embryonic development; in other words, Hox genes dictate where body parts will go.

The Hox genes sit clustered together in the cell’s DNA, surrounded by long sequences of DNA that contain no genes whatsoever. However, these seemingly empty spaces of DNA actually contain small, discrete sequences that have been shown to bind and interact with the Hox gene cluster and regulate the Hox genes. The question is, since Hox genes are responsible for different tissues and organs, are they controlled in the same way?

An EPFL team of researchers led by Denis Duboule has now shown that these long DNA sequences actually enable Hox genes to be expressed in multiple tissues in the fetus. This allows the Hox genes to produce diverse organs of the developing body. The researchers call the long DNA sequences a “regulatory archipelago”, while the small, discrete sequences are “islands”. The idea is that the archipelago folds over the cluster of Hox genes and binds to them with its “islands”. Then it subtly shifts around to activate the Hox genes needed for that particular tissue or organ.

To go into more detail, when the archipelago covers the Hox genes, it forms a DNA complex. This is in turn controlled by chemical signals coming from surrounding cells. These signals act on the 3D structure of the DNA complex, causing changes in its structure. Though subtle, the changes nonetheless determine which combinations of Hox genes are going to be expressed at any given time. In this way, the same Hox genes can be used to regulate different structures in the body.

In this study, lead author Nicolas Lonfat focused on one member of the Hox gene family, Hoxd13, which controls the development of digits (fingers) and genitals in mice. He discovered two DNA “island” sequences, one interacting only with Hoxd13 in digits, while the other in exclusively in genitals. This way, he was able to connect each “island” with the part of the body it controlled.

The study has significant implications of how we understand the evolution of gene regulation. “Since animals with four limbs are late in terms of evolution, it would seem as if nature ‘hijacked’ some of these genes to make genitals and digits,” says Denis Duboule. In addition, the findings help explain how congenital diseases and deformities arise, such as hand-foot-genital syndrome, which results when a Hox gene is incorrectly regulated. As Duboule explains: “The ‘regulatory archipelago’ is a very precise mechanism that allows tremendous efficiency for the cell. The downside, however, is that is it is fragile and susceptible to errors.”

The study’s authors suggest that this system of gene control extends beyond developmental genes and variations of it may exist for all pleiotropic genes.

This work represents a collaboration of EPFL with the University of Geneva.

Reference

Lonfat N, Montavon T, Darbellay F, Gitto S, Duboule D. Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci. Science