10. DNA Packaging (1,216;8/29;pre-RL)

Most nucleated cells in your body contain two sets of chromosomes—one inherited from your mother and one from your father. Together, these cells' nuclei contain more than 6 billion base pairs of DNA. Although different kinds of cells use different genes depending on their role in the body, most contain essentially the same two genomes.

That creates a problem.

If we could stretch out the DNA in a typical human cell nucleus it would extend nearly six feet. Yet the nucleus that holds it is only about 5–10 micrometers across—far too small to see with the unaided eye. Six feet of DNA in a space that small. How is that possible? And, furthermore, the DNA must remain usable while it’s packaged this tightly.

Part of the answer is that DNA is very, very thin—about 2 nanometers across, which is smaller than the wavelength of visible light. But thinness alone isn’t enough. The complete answer must include packaging.

DNA isn't just crammed into the nucleus. It's carefully wound, wrapped and looped. And it's not just about fitting DNA into a small space. The way DNA is packaged plays a major role in determining which genes are available to be transcribed.

Packaging at several scales

DNA packaging operates at several scales. At the smallest scale, DNA wraps around small protein spools. Chains of this spooled DNA then fold and interact in ways that compact the DNA further. At larger scales, the compacted spools are organized into loops and larger structures. Finally, during cell division, each chromosome becomes dramatically more condensed.

Thinking of DNA as being packaged at these discrete levels is useful for understanding the packaging of the genome, but current thinking is that the packaging is not as neat or uniform as textbook diagrams sometimes suggest. But we’ll think in terms of these levels to get the idea.

Level 1: Nucleosomes—DNA wrapped around protein spools

At the first level of packaging, DNA wraps around small complexes of proteins called histones, much like thread wrapped around a spool. These DNA spools are called nucleosomes. The histone proteins also have flexible molecular “tails” that can be chemically modified, helping regulate how the surrounding DNA is used.

Each nucleosome consists of eight histone proteins—two each of four different kinds—around which 147 base pairs of DNA are wrapped nearly twice. Between the nucleosomes are short stretches of exposed DNA. DNA together with its associated histone proteins is called chromatin. At its least compact, chromatin is often described as looking like “beads on a string.”

It’s tempting to think of this packaging as static. It isn’t.

Nucleosomes are dynamic. DNA at their edges repeatedly unwraps and rewraps—a motion sometimes called “breathing”—briefly exposing sequences that would otherwise be covered. Specialized protein complexes can also slide, restructure or remove nucleosomes, changing which portions of DNA are accessible. This constant activity means that even packaged DNA can be made available when the cell needs to use it.

Level 2: Local folding and compaction

The beads-on-a-string structure does not remain fully extended. Neighboring nucleosomes interact with each other, and the chain bends, folds and packs together, producing regions that are more or less compact.

Traditional textbook diagrams often show nucleosomes folding into a uniform structure called the 30-nanometer fiber. Such fibers can form under certain conditions, but researchers are not sure how commonly they exist inside ordinary living cells. Chromatin in the nucleus generally appears more irregular and variable than traditional textbook diagrams suggest.

Level 3: Looping—organization and contact

At a larger scale, protein complexes organize the folded or fibrous chromatin into large loops, many containing tens to hundreds of thousands of base pairs. These loops help divide the genome into neighborhoods within which otherwise distant DNA regions are more likely to be close to and encounter one another. In some cases, looping brings a gene close to regulatory DNA that helps control its transcription.

These loops are not permanently tied in place. Many form, disappear and reform as organizing proteins move along or detach from the chromatin. Looping therefore contributes to both the physical organization of the genome and the regulation of access to particular regions.

Chemical “signposts” on histones

Another layer of control operates through chemical modifications made to histones. The flexible tails of the histone proteins around which DNA is wrapped can be chemically modified in different ways. The cell has specific enzymes that add and remove these modifications.

Sometimes these changes directly affect how tightly DNA is wrapped. But more often, they act as signals—markers that recruit other proteins to that location. These proteins can be involved in transcription, DNA repair, or the opening and compaction of chromatin. In this way, histone modifications act like signposts, guiding diverse cellular processes to specific regions of the genome.

Scientists sometimes refer to these patterns of modifications as a "histone code"--a set of signals that influences how that stretch of DNA will be used. The metaphor should not be taken too literally, though. Unlike the genetic code, which is predictable enough that we can summarize it in a codon table, a particular histone modification does not always have one fixed meaning. Its effect can depend on its location, its molecular surroundings and the other modifications nearby.

Additional layers of control

The cell has other ways of controlling DNA accessibility, too. In some nucleosomes, standard histones are replaced with alternative versions called histone variants. These variants can alter a nucleosome’s stability, its interactions with other proteins, or the way that region of DNA is used. 

Even the position of DNA within the nucleus matters. Each chromosome tends to occupy its own region, known as a chromosome territory. Gene-rich chromosomes and active regions are often found closer to the nuclear interior, while inactive, densely packed chromatin is frequently associated with the nuclear periphery. These are tendencies, however, not absolute rules.

A dynamic system

As mentioned, DNA packaging is not static. Nucleosomes breathe and are repositioned. Chromatin changes its degree of compaction. Loops form and disappear. Chemical modifications are added and removed, while proteins continually bind to chromatin and detach from it.

The genome is not merely stored. Its organization changes as the cell transcribes genes, repairs DNA damage, replicates its genome or prepares to divide. During replication, for example, nucleosomes ahead of the replication machinery must be partially dismantled and then reassembled on the newly synthesized DNA.

Level 4: Maximum compaction during cell division

The final and most dramatic level of packaging occurs during cell division. After the genomic DNA has been replicated, protein complexes reorganize and compact each chromosome into tightly packed arrays of loops. This produces the familiar X-shaped structures seen in microscope images. Each X consists of two identical sister chromatids (separate but identical chromosomes) that will eventually be separated into the two daughter cells.

In this highly compacted form, DNA is no longer readily accessible for transcription. Gene expression largely pauses or, at least, becomes greatly reduced. The priority is not reading the DNA, but safely separating it into two daughter cells.

At every level--from nucleosomes to loops to entire chromosomes--the way DNA is packaged helps determine which genes are more or less accessible and when they can be used. The genome is not just a sequence of letters. It's a dynamic, three-dimensional structure that's constantly being reorganized to meet the cell's needs.