Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci

摘要

Most animals are symmetrical about an imaginary line that runs from the head to the tail. A family of genes called the Hox family ensures that the cells in an animal embryo develop into the correct body parts along this head-to-tail axis. Hox genes—which are found in animals as diverse as flies and humans—are often clustered on the chromosomes, and their order within a cluster affects when and where each Hox gene is ‘switched on’. In mammals, Hox genes at one end of a cluster are switched on first and along almost the entire length of the embryo. Hox genes near the other end of the cluster are expressed later and only towards the hind end of the animal. And Hox genes at the furthest end of the cluster are expressed last and in the very tip of the developing tail. The time when a Hox gene is expressed depends largely on its relative position within the gene cluster. However, it is not clear how the ordering of the genes within a cluster is translated into a schedule whereby the genes are sequentially switched on during development. Much of the DNA in a chromosome is wrapped around proteins to form a structure called chromatin; chromatin is normally tightly packed, but ‘unpacking’ it allows the genes to be accessed and switched on. Now, Noordermeer et al. have used a technique called ‘circular chromosome conformation capture’ to follow how the packing of the chromosomes that carry the Hox gene clusters changes during embryonic development. Harvesting cells from mouse embryos of different ages, and cross-linking the DNA to the proteins, allowed those genes that are packed in the chromatin to be distinguished from those that have been unpacked and activated. When the embryo is still just a ball of almost identical cells, all the Hox genes are switched off and packed into inactive chromatin. However, Noordermeer et al. found that, as the embryo develops and when each Hox gene is switched on in turn, the relevant region of DNA is also unpacked and moved into more active chromatin. This mechanism likely prevents Hox genes that direct the development of the hind end of the mouse from being switched on too early, and hence it avoids body parts being misidentified and developing incorrectly. Further, the patterns of active chromatin vs inactive chromatin can be fixed at each section along head-to-tail axis, such that it will be memorized in all daughter cells produced subsequently from each particular body section. Future challenges will be to uncover the trigger behind the step-wise transition of every Hox gene from inactive chromatin to active chromatin, and to crack the underlying ‘clock’ that controls the timing of this process.