The genetic material within a human cell measures approximately two meters long. This immense length of double-stranded DNA must be precisely contained and organized within the microscopic confines of the cell nucleus, which is only about 5 to 10 micrometers in diameter. The process of packaging this huge molecule achieves a compaction ratio of nearly 10,000-fold by the time of cell division. This layered organization, known as chromatin, is fundamental to all cellular processes, including gene expression, DNA replication, and accurate cell division.
The First Level of Condensation: Nucleosomes
The first step in DNA packaging involves histones, which are small, positively charged proteins that strongly attract the negatively charged phosphate backbone of DNA. Four types of core histones—H2A, H2B, H3, and H4—assemble into an octamer consisting of two copies of each type.
The DNA molecule then wraps tightly around this histone octamer spool approximately 1.67 times, covering about 146 to 147 base pairs. This structure is called the nucleosome core particle. Nucleosomes are linked together by a short stretch of free DNA, called linker DNA, creating a structure that resembles “beads on a string.” This 11-nanometer-diameter fiber reduces the length of the DNA molecule by roughly seven times.
Intermediate Coiling and the 30nm Fiber
The “beads on a string” nucleosome chain undergoes further condensation to form the 30-nanometer (nm) chromatin fiber. While this transition increases compaction, the exact, uniform structure of this fiber in living cells remains a topic of scientific debate. The solenoid model suggests that nucleosomes stack sequentially in a helical path, forming a continuous coil.
The zigzag model suggests that linker DNA connects non-adjacent nucleosomes across the central axis, resulting in two staggered stacks that twist together. Both models require the linker histone H1, which binds to the linker DNA region and stabilizes the higher-order structure by promoting inter-nucleosome interactions. The formation of this 30nm fiber is achieved through interactions involving the N-terminal tails of the core histones and the H1 linker histone.
Functional States of Chromatin
Beyond compaction, the organization of DNA into chromatin dictates whether genes can be expressed. Chromatin exists in functional states that regulate access to the genetic code. The less condensed form is euchromatin, characterized by a loose, open structure that allows cellular machinery to easily access genes for transcription.
The opposite state is heterochromatin, which is highly condensed and densely packed, rendering the genes within it transcriptionally inactive. The transition between these states is mediated by chemical modifications, occurring on the tails of the histone proteins. For instance, the addition of acetyl groups to lysine residues (acetylation) neutralizes their positive charge, weakening the histone-DNA interaction and promoting the open euchromatin state. Conversely, certain methylation marks can lead to tighter packing and the formation of the closed heterochromatin structure.
Final Compaction into Metaphase Chromosomes
The final level of DNA packaging occurs before a cell divides, resulting in metaphase chromosomes. This compaction is necessary to ensure that the duplicated genetic material is segregated accurately without tangling or breakage. The process requires reorganization of the 30nm fiber and involves specialized scaffolding protein complexes.
A major player in this final stage is the condensin complex, which works to fold and coil the chromatin fiber into large, organized loops. Condensin, existing in two forms (Condensin I and Condensin II), functions by actively compacting the chromatin along a central axis. This final looping and scaffolding action achieves the characteristic, highly compact structure of the mitotic chromosome.