Available online at www.sciencedirect.com Physical nuclear organization: loops and entropy Dieter W Heermann 1,2 In vivo, chromosomes due to dynamic association with protein factors fold to form three-dimensional structures. Many experiments have paved the way to understand folding and the nuclear architecture of the genome. On the basis of these experiments and models a fundamental understanding of the key principles that drive the physical organization has become possible through the concepts of loop and entropy. Using the concept of loop, models are now able to reproduce the results from several of the experiments within the framework of loop and entropy. Linking biological function to structure they moreover are able to make predictions. Addresses 1 Theoretical Biophysics Group, Institute for Theoretical Physics, University of Heidelberg, Philosophenweg 19, D-69120 Heidelberg, Germany 2 The Jackson Laboratory, Bar Harbor, ME, USA Corresponding author: Heermann, Dieter W (heermann@tphys.uni-heidelberg.de) Current Opinion in Cell Biology 2011, 23:332–337 This review comes from a themed issue on Nucleus and gene expression Edited by Martin W Hetzer and Giacomo Cavalli Available online 5 April 2011 0955-0674/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2011.03.010 Loops What are the physical organizing principles of chromo- somes that determine the nuclear architecture in inter- phase? Hence we ask: Why do chromosomes not completely mix, i.e., why do chromosomes organize into territories? Why is there an internal segregation into micro-domains within a chromosome? Can we understand how the physical architecture relates to biological pro- cesses and how this structure is maintained? Key to understand the above posed questions is the entropic repulsion between loops. So we first look into chromosomal loops. Several recent reviews have addressed different aspects of chromosome looping and the reader is referred to these [1–5]. The picture that is emerging is that the existence of loops is undisputed in interphase chromosomes. Further, loops exist on all scales, i.e., ranging with respect to genomic distance between proximal fiber points from hundreds of base pairs to tenths of mega base pairs [6  ]. So then, what constitutes a loop? On the scale of about 150 bp we find loops in the form of nucleosomes (cf. Figure 1). We can view the nucleosome as the smallest organizational loop of the chromosome. Here the histone protein H1 is the loop provider that connects genomically ‘distant’ parts of DNA to form a loop. Clearly one of the roles of this form of a loop is to physically compactify DNA to reduce the overall length of the chain. A byproduct of this is that elements along the DNA that have been farther apart than say 150 bp are now physically closer, paving the way for possible physical proximity of genomically distal parts (cf. Figure 1). Important to note is that this organization is dynamic. Displacing of nucleosomes along the DNA, removing and transferring nucleosomes to non-adjacent regions of DNA as well as nucleosome-free regions remodels this loop structure [7–11]. This in turn leads to conformational changes of the entire chromosome. In turn the overall conformation of a chromosome is dynamic. A not yet fully explored slightly larger genomic length scale is the interaction between the histones due to enzyme- catalyzed modifications of these proteins. They alter the local chromatin organization and can be viewed as provid- ing physical proximity and thus give rise to a subtle form of looping. On this scale chromosome conformation capture experiments and models [12,13] suggest the necessity of loops in order to explain the flexibility of the fiber. Moving further up in genomic length scale larger loops are formed during the assembly of transcription factories, nuclear structures that contain several genes [14  –16]. There is growing evidence that distant regulatory elements make direct contact with either the promoter or another regulatory element of the gene they control. Two well- studied examples are the looping of the developmentally controlled beta-globin locus and the imprinted H19-Igf2 locus [17–21]. Here, looping can result in gene activation or in its inhibition. Hence chromatin loops can be found at both active and repressed genes and are not limited to enhancer-promoter interactions but can also involve insu- lator elements. Other long-range looping mechanisms in- clude the clustering of distant polycomb response elements in Drosophila [3  ,22] and of insulator elements found in various higher eukaryotes [23]. To sum up, loops vary in length from hundreds of base pairs to up to tens of Mb [6  ,24]. Thus the picture is that loops organize the chromosome hierarchically as depicted in Current Opinion in Cell Biology 2011, 23:332–337 www.sciencedirect.com