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? For the first time molecular machines that organize the genome and control the DNA accessibility – the “chromatin remodelers” – have been studied in living cells by scientists from the DKFZ in Heidelberg and the University of Regensburg. Their misregulation can severely impair cell differentiation and is associated with the development of leukemia and other forms of cancer.

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, researchers in the group of Karsten Rippe at the DKFZ together with that of Gernot Längst at the University of Regensburg 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 typically for only a tenth or a hundredth of a second and then detaches to test another nucleosome until it finds one that carries some special feature to bind it more tightly. Only if the two of them fit together well, the remodeler gets hooked up to the nucleosome: It stays for seconds or even minutes to shift it to a new position on the DNA, then dissociates and moves on. In special cases, for example if the DNA is damaged and has to be repaired many nucleosomes have to be repositioned and remodelers accumulate at this “activity hotspot”. Since remodelers are highly abundant and they never stop searching it takes them only a few seconds to recognize the DNA damage signals that keep them there – but only for a while. As Fabian Erdel, a graduate student at the DKFZ and the lead author of the study 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.“ Aberrant chromatin remodeler activity in several types of cancers is related to a misinterpretation of epigenetic nucleosome signals. Thus, the next challenge in understanding their function will be to decipher the signals that make them stick to one nucleosome and not the others.

Erdel, F., Schubert, T., Marth, C., Längst, G. and Rippe, K. (2010) Human ISWI chromatin-remodeling complexes sample nucleosomes via transient binding reactions and become immobilized at active sites. Proceedings of the National Academy of Sciences of the USA, published online ahead of print, October 25, 2010.

PD Dr. Karsten Rippe
Deutsches Krebsforschungszentrum & BioQuant
Division of Genome Organization & Function (B066)
Im Neuenheimer Feld 280
D-69120 Heidelberg
Tel.: +49-6221-54-51376 Fax: +49-6221-54-51487
e-mail: Karsten.Rippe@dkfz.de
http://malone.bioquant.uni-heidelberg.de