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9.11: Packing DNA into a cell

An important part of our approach to biology is to think concretely about the molecules we are considering. Nowhere is this more important than with DNA. DNA molecules are very long and cells, even the largest cells, are (generally)small. For example, a typical bacterium is roughly cylindrical and around 2μm in length and about 1μm in circumference. Based on the structure of DNA, each base pair is about 0.34 nm in length. A kilobase (that is, 103 base pairs) of DNA is therefore about 0.34 μm in length. A bacterium, like E. coli, has ~ 3 x 106 base pairs of DNA – that is a DNA molecule almost a millimeter in length, or about 500 times the length of the cell in which it finds itself. That implies that at the very least the DNA has to be folded back on itself at least 250 times. A human cell has ~6000 times more DNA, that is a total length of greater than 2 meters (per cell), and this lenght of DNA has to fit into a nucleus that is ~10 μm in diameter. In both cases, the DNA has to be folded and packaged in ways that allow it to fit and yet still be accessible to the various proteins involved in the regulation of gene expression and the replication of DNA. To accomplish this, the DNA molecule is associated with specific proteins; the resulting DNA:protein complex is known as chromatin.

The study of how DNA is regulated is the general topic of epigenetics (on top of genetics), while genetics refers to the genetic information itself, the sequence of DNA molecules. If you consider a particular gene (based on our previous discussions) you will realize that to be expressed, transcription factor proteins must be able to find (by diffusion) and bind to specific regions (defined by their sequences) of the DNA in the gene’s regulatory region(s). But the way the DNA is organized into chromatin, particularly in eukaryotic cells, can dramatically influence the ability of transcription factors to interact with and bind to their regulatory sequences. For example, if a gene’s regulatory regions are inaccessible to protein binding because of the structure of the chromatin, the gene will be “off” (unexpressed) even if the transcription factors that would normally turn it on are present and active. As with essentially all biological systems, the interactions between DNA and various proteins can be regulated.

Different types of cells can often have their DNA organized differently through the differential expression and activity of genes involved in opening up (making accessible) or closing down (making inaccessible) regions of DNA. Accessible, transcriptionally active regions of DNA are known as euchromatin while DNA packaged so that the DNA is inaccessible is known as heterochromatin. A particularly dramatic example of this process occurs in female mammals. The X chromosome contains ~1100 genes that play important roles in both males and females278. But the level of gene expression is (generally) influenced by the number of copies of a particular gene. While various mechanisms can compensate for differences in gene copy number, this is not always the case. For example, there are genes in which the mutational inactivation of one of the two copies leads to a distinct phenotype, a situation known as haploinsufficiency. This raises issues for genes located on the X chromosome, since XX organisms have two copies of these genes, while XY organisms have only one279. While one could imagine a mechanism that increased expression of genes on the male’s single X chromosome, the actual mechanism used is to inhibit expression of genes on one of the female’s two X chromosomes. In each XX cell, one of the two X chromosomes is packed into a heterochromatic state, more or less permanently. It is known as a Barr body. The decision as to which X chromosome is packed away (“inactivated”) is made in the early embryo and appears to be stochastic - that means that it is equally likely that in any particular cell, either the X chromosome inherited from the mother or the X chromosome inherited from the father may be inactivated (made heterochromatic). Importantly, once made this choice is inherited, the offspring of a cell will maintain the active/inactivated states of the X chromosomes of its parental cell. Once the inactivation event occurs it is inherited vertically280. The result is that XX females are epigenetic mosaics, they are made of clones of cells in which either one or the other of their X chromosomes have been inactivated. Many epigenetic events can persist through DNA replication and cell division, so these states can be inherited through the soma. A question remains whether epigenetic states can be transmitted through meiosis and into the next generation281. Typically most epigenetic information is reset during the process of embryonic development.

References

278 Human Genome Project: Chromosome X: http://www.sanger.ac.uk/about/history/hgp/chrx.html

279 The Y chromosome is not that serious an issue, since its ~50 genes are primarily involved in producing the male phenotype.

280 X Chromosome: X Inactivation: http://www.nature.com/scitable/topic...activation-323

281 Identification of genes preventing transgenerational transmission of stress-induced epigenetic states: http://www.ncbi.nlm.nih.gov/pubmed/24912148

Contributors

  • Michael W. Klymkowsky (University of Colorado Boulder) and Melanie M. Cooper (Michigan State University) with significant contributions by Emina Begovic & some editorial assistance of Rebecca Klymkowsky.