In search of Mr. Right – speed dating of chromatin remodelers in living cells
How does a cell regulate the access to the information encoded in its DNA? We conducted the first study of the molecular machines known as “chromatin remodelers” in living cells in collaboration with the group of Gernot Längst at the University of Regensburg. We found that they spend much of their time rapidly searching for their nucleosome soulmates. And, just like desperate singles at a Speed Dating party, they keep at it until they find the right one.
The human genome is organized by wrapping the DNA around small histone proteins. These globular “nucleosome” complexes are connected by segments of protein free linker DNA into a chain with a pearl necklace like structure. Gene activation requires freely accessible DNA, and genes can be inactivated by occluding DNA parts within a nucleosome complex. Hence, the nucleosome positions determine a read out pattern: Information in the DNA linker region between nucleosomes is more easily accessible as opposed to sequences that are blocked by histone-DNA interactions. Energy-consuming molecular machines, the chromatin remodelers, can move nucleosomes along the DNA chain to establish these patterns on newly synthesized DNA during cell division, and to switch between “on” and “off” states of a gene. They are an essential part of a regulatory network that allows the cell to select specific programs to differentiate into a muscle cell, a nerve cell or a skin cell from the identical genetic information. By studying chromatin remodelers in living cells we found out that about a million remodeler complexes exist in a single human cell nucleus and that they move surprisingly fast. But how do they find “the right” nucleosome?
A given remodeler binds to a nucleosome for only about 1/10th to 1/100th of a second, and then detaches to test another until it finds the perfect one that binds it tightly. If the two fit together well, the remodeler hooks up to the nucleosome: staying for seconds or even minutes to shift it to a new position on the DNA, before it dissociates. In special cases, like when DNA is damaged and needs repaired, many nucleosomes are repositioned and remodelers will accumulate at this “activity hotspot”. Because there are so many remodelers, and they are always searching for matches, it takes them only a few seconds to recognize the DNA damage signals and spring into action. As lead author Fabian Erdel from DKFZ puts it: “Remodelers come and go and you can hardly keep them in place. But if you need them they show up in no time”.
The misinterpretation of epigenetic nucleosome signals due to aberrant chromatin remodeler activity is linked to several types of cancers, so the next challenge will be to decipher how different signals make remodelers stick to one nucleosome but not others.
Erdel, F., Schubert, T., Marth, C., Längst, G. & Rippe, K. (2010). Human ISWI chromatin-remodeling complexes sample nucleosomes via transient binding reactions and become immobilized at active sites. Proc. Natl. Acad. Sci. USA, published online 25 October 2010. Abstract | Reprint (1.4 MB) | Comment