Biology Worthy of Life
An experiment in revivifying biology
The Complex Performance of the Three-Dimensional Chromosome
Stephen L. Talbott
Time was when biologists inquiring about the role of chromosomes scarcely looked beyond the inert, informational sequence of DNA “letters” (nucleotide bases). These supposedly represented something like the 0s and 1s of a computer code — in this case, the instructions for building an organism.
That kind of thinking has proven hard for biologists to escape, and continues to weigh heavily upon the literature. Nevertheless, the buzzwords in today’s laboratories are all about the significant movement and form of chromosomes within the three-dimensional nuclear space. In a recent review in the journal Cell, molecular biologists Wendy Bickmore and Bas van Steensel opine that “the overall spatial organization of the mammalian genome is a fundamental state upon which genome function is then largely played out”. And another biologist, Erez Aiden, writing about the spatial dynamics and organization of chromosomes in the nucleus, characterizes what goes on as “epigenetics through origami”.
Some Definitions
The word “epigenetics” is used in various ways. In general, it is probably best to take it very broadly as referring to all the ways the organism manages its genome without changing the actual DNA sequence. Origami is the Japanese art of (often very elaborate) paper folding. A megabase is a measure equalling one million nucleotide bases, or “letters”, of the sequence along a single strand of DNA or RNA, or one million base pairs along a double-strand.
Some recent work focuses on just one aspect of the chromosome’s dynamism: its subdivision into functional domains with distinctive physical and dynamic characteristics.
If you want to imagine how the 46 human chromosomes exist inside a typical cell nucleus, the usual advice is to picture 24 miles (40 km) of extremely thin thread cut into 46 pieces, each averaging about a half mile long and packed into a tennis ball. Maintaining order and keeping things untangled, while also allowing dynamic movements and interactions between sometimes distant chromosomal regions, is a problem researchers have hardly begun to sort out as yet.
The problem has only become more complex in recent years as researchers have uncovered ever more subtlety in the organization and dynamics of chromosomes. It’s been known for some time that individual chromosomes tend to occupy separate, though somewhat intermingling, territories. But more recent researches are revealing many additional levels of organization within chromosomes, with each level characterized by its own sort of dynamism. Much work to date has focused on roughly megabase-sized interacting regions known as “topologically associated domains”, or TADs. These are present throughout the genome and are generally invariant across cell types.
As techniques are refined, smaller regions can be looked for. One group of researchers now reports that, upon examining 7 TADs in 2 cell types, they found over 60 sub-TADs of varying sizes. Hundreds of long-range interactions occurred between these smaller regions — generally achieved by means of movements known as “chromosome looping”. These interactions often differed between cell types. Moreover, the formation of loops was facilitated by protein anchors, and the combination of proteins differed according to the scale of the looping domains.
This kind of activity gives us one angle of view upon how DNA participates in, and makes its contribution to, the life of the organism. It’s a far cry from the usual picture of an abstract set of computer-like codes.
All in all, the work is uncovering what the researchers refer to as a “complex hierarchy” of organizational features in chromosomes. This organization is obviously of functional importance for gene expression, it is established by the larger context, and it is not unilaterally dictated by the genetic sequence. When researchers refer to the “choreography” of the cell nucleus and the “dance” of chromosomes (as they sometimes do), their language is closer to being literal than many have imagined.
Biologists should be asking themselves: If such choreography is how the organism lives and performs at the molecular level, what does that mean for the nature of molecular biological explanation? How can we understand a dance or any other play of form without drawing, at least in part, on aesthetic aspects of cognition?
Aiden, Erez Lieberman (2011). “Zoom!”, Science vol. 334 (Dec. 2), pp. 1222-3. doi:10.1126/science.1216288
Phillips-Cremins, Jennifer E., Michael E. G. Sauria, Amartya Sanyal, et al. (2013). “Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment”, Cell vol. 153 (June 6), pp. 1281–95. doi:10.1016/j.cell.2013.04.053
Bodnar, Megan S. and David L. Spector (2013). “Chromatin Meets Its Organizers”, Cell vol. 153 (June 6), pp. 1187-9. doi:10.1016/j.cell.2013.05.030
Further information: For much more about how chromosomes participate in the living qualities of the cell and organism, see the section entitled “The Dynamic Chromosome” (and following sections) in “Getting Over the Code Delusion”: http://BiologyWorthyofLife/mqual/genome_4.htmThis document: https://bwo.life/org/comm/ar/2013/performance-of-3d-chromosome_2.htm
Steve Talbott :: The Complex Performance of the Three-Dimensional Chromosome