Review
Condensed DNA: Condensing the concepts

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Abstract

DNA is stored in vivo in a highly compact, so-called condensed phase, where gene regulatory processes are governed by the intricate interplay between different states of DNA compaction. These systems often have surprising properties, which one would not predict from classical concepts of dilute solutions. The mechanistic details of DNA packing are essential for its functioning, as revealed by the recent developments coming from biochemistry, electrostatics, statistical mechanics, and molecular and cell biology. Different aspects of condensed DNA behavior are linked to each other, but the links are often hidden in the bulk of experimental and theoretical details. Here we try to condense some of these concepts and provide interconnections between the different fields. After a brief description of main experimental features of DNA condensation inside viruses, bacteria, eukaryotes and the test tube, main theoretical approaches for the description of these systems are presented. We end up with an extended discussion of the role of DNA condensation in the context of gene regulation and mention potential applications of DNA condensation in gene therapy and biotechnology.

Introduction

Storage and processing of genetic information encoded in DNA is governed by a number of compounds, which bind, bend, loop, modify DNA and assemble on the double helix, recognize each other and target new DNA binders (Fig. 1). These events are further complicated by the fact that they happen in vivo in a highly compact, so-called condensed DNA state. Scientists have been dealing with condensed DNA since the discovery of nucleic acids. However, only recently with the development of adequate tools for the single-molecule and whole-genome analysis, it has became possible to connect classical bulk experiments to mechanistic details of gene regulation in vivo. This has led to a number of new concepts and the reevaluation of some of the old ones. The purpose of this review is to provide what we believe are the most exciting concepts, which obviously does not reflect the whole body of the literature. For more extensive data-oriented literature overview see the recent books with the focus on DNA condensation in vitro (Dias and Lindman, 2008) or in vivo (Rippe, in press) and older reviews devoted to DNA condensation (Bloomfield, 1996, Bloomfield, 1997, Gelbart et al., 2000, Hud and Vilfan, 2005, Schiessel, 2003, Strey et al., 1998, Vijayanathan et al., 2002, Yoshikawa, 2001, Yoshikawa and Yoshikawa, 2002). We will start with biological concepts arising from DNA packing in viruses, bacteria and eukaryotes, then proceed to DNA condensation in vitro and its theoretical modeling, and finally discuss the role of DNA condensation in the context of gene regulation in living systems and its potential biomedical applications.

Section snippets

The concept of DNA condensation

DNA is a long and strongly charged heteropolymer. It bears on average one elementary negative charge per each 0.17 nm of the double helix. DNA diameter is about 2 nm, while the length of a stretched single-molecule may be up to several dozens of centimeters depending on the organism (Bloomfield et al., 2000). Many features of the DNA double helix contribute to its large stiffness, including the mechanical properties of the sugar–phosphate backbone, electrostatic repulsion between phosphates,

DNA condensation in viruses

In viruses and bacteriophages, the DNA or RNA is surrounded by a protein capsid, sometimes further enveloped by a lipid membrane. Double-stranded DNA is stored inside the capsid in the form of a spool, which can have different types of coiling (Hud, 1995) leading to different types of liquid-crystalline packing (Earnshaw and Harrison, 1977, Hud and Downing, 2001, Knobler and Gelbart, 2009, Leforestier and Livolant, 2009). This packing can change from hexagonal to cholesteric to isotropic at

DNA condensation in bacteria

Bacterial DNA is packed with the help of polyamines and proteins. Protein-associated DNA occupies about 1/4 of the intracellular volume forming a concentrated viscous phase with liquid-crystalline properties, called the nucleoid (Cunha et al., 2001, Wiggins et al., 2010). Similar DNA packaging exists also in chloroplasts (Sekine et al., 2002) and mitochondria (Friddle et al., 2004). Bacterial DNA is sometimes referred to as the bacterial chromosome (Saier, 2008). In fact, the bacterial nucleoid

DNA condensation in eukaryotes

In comparison with bacteria or viruses, eukaryotic chromatin is the “state of the art” of DNA condensation, and also a large field of scientific efforts, which we will only briefly mention here. Eukaryotic DNA with a typical length of dozens of centimeters should be orderly packed to be readily accessible inside the micrometer-size nucleus. Thus DNA is always “condensed” in chromatin, but there are different states of DNA condensation. In primitive unicellular eukaryotes such as

Experimental methods

Most of our knowledge about condensed DNA states comes from comparatively simple in vitro experiments started in the 1970s (Gosule and Shellman, 1976, Lerman, 1971). In such experiments, DNA is compacted by adding different condensing agents, from simple inorganic ions to large macromolecules, which represent important model systems to understand DNA functioning in vivo and also to achieve controlled drug delivery in gene therapy. During four decades of such experiments, DNA condensation has

The coil–globule transition

Condensation of long double-helical DNAs is a sharp phase transition, which takes place within a narrow interval of ligand concentrations (Bloomfield, 1996, Bloomfield, 1997, Yoshikawa et al., 1996). Unlike protein folding, the general features of the DNA coil–globule transition such as the topology of the condensate are mainly determined by the average polymer and solution properties (DNA length, concentration, solution content and temperature) and not by the DNA sequence. On the other hand,

DNA condensation in the context of gene regulation

Most nowadays descriptions of gene regulation are based on the approximations of equilibrium binding in dilute solutions, although it is clear that these assumptions are in fact violated in chromatin (Michel, 2010, Teif, 2010). The dilute solution approximation is violated for two reasons. First, the chromatin content is far from being dilute, and second, the numbers of the participating molecules are sometimes so small, that it does not make sense to talk about the bulk concentrations. Further

Potential applications in medicine and biotechnology

The main potential application of DNA condensation in medicine is its use for gene delivery in gene therapy. The main problems in gene therapy are target recognition (what in the genome should be targeted by artificial DNA or RNA constructs), target modification (the way how the drug acts on the target), and the delivery of the DNA-targeted drug to the cell (here DNA condensation comes into play). Usually, the search for new drug delivery agents is performed by experimental screening of

Summary

The study of DNA condensation has already significantly enriched fundamental science by several new concepts (Fig. 8). We have studied above, how the properties of the DNA as a polymer and as a polyelectrolyte fine-tune its properties as a carrier of the genetic text, which results in the stepwise increase of the complexity and the appearance of principally new collective properties, which neither the elastic polymer nor the polyelectrolyte or the string of text would have on its own. Adding

Acknowledgments

We are grateful to Jean-Louis Sikorav, Arach Goldar, Karsten Rippe, Dmitri Lando and anonymous reviewers for discussions and valuable suggestions and to Alex Beath, Jan-Philipp Mallm and Fabian Erdel for critical reading the manuscript. We apologize for many researchers whose work was not mentioned due to space limitations. VT acknowledges support by the German CellNetworks – Cluster of Excellence (EXC81) and Belarus National Foundation for Fundamental Research (grant #B10M-060). Part of this

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