The word ‘compaction’ is one that in my mind conjures up images of vacations long-passed when I would cram as many clothes as I could into the smallest suitcases I could find. Such a task has become even more irksome in recent years with the hefty restrictions in place that limit the amount of luggage we can now take onto airplanes. But in at least one context- that of DNA biology- compaction refers to something much more exquisite and desirable.
The diploid eukaryotic cell faces the challenge of squeezing and compacting about two meters of DNA into the tiny space of the nucleus (Ref 1). As DNA structuralists Chris Calladine and Horace Drew described many years ago, DNA in most eukaryotic genomes is compressed 10,000-fold (Ref 2). This is partially achieved by highly specialized proteins called histones (denoted as H1, H2a, H2b, H3, H4) around which the DNA is wrapped (Ref 2). The resulting DNA/Histone complex, called a nucleosome subunit, is repeated tens of millions of times across the human genome to form chromatin, which is further compacted into ordered fibers 250-300 Angstroms in diameter (Refs 1-4). Such compaction is crucial if the billions of base pairs of DNA that make up, say, the human genome are to fit into the tiny space of the nucleus (Ref 1).
Much work still needs to be done to elucidate the precise mechanisms through which DNA becomes accessible to RNA polymerases and subsequently gets transcribed. Yet in a seminal paper co-authored by Wistar Institute molecular biologist Ronen Marmorstein, it has become clear that this increased accessibility of chromosomal DNA to the transcription machinery is dependent upon complex modifications of the histone proteins- a feature of transcriptional regulation that forms the basis of what is more commonly referred to as the ‘histone code’ (Refs 3-5).
Several classes of histone modification have now been documented in the scientific literature notably acetylation, phosphorylation and methylation (Ref 3). Of all, acetylation is perhaps the best characterized within the context of transcriptional regulation (Ref 3) although H3 and H4 acetylation also appears to play a key role in other cellular processes such as DNA replication (Ref 4). The synergistic nature of histone modifications has been extensively discussed (Refs 4,7). We now know for example that methylated, non-acetylated H4 tends to be associated with regions of the genome that are transcriptionally inactive. Conversely phosphorylated, acetylated H3 is usually present in transcriptionally active regions (Refs 4,6).
Histone modifications may be sensitive to external environmental cues, resulting in a rapid modulation of gene expression (Ref 7). Moreover they can exert long term, stable effects, maintaining DNA in either a transcriptionally active or inactive state over many rounds of cell division (Ref 7). Importantly, the histone code parallels the everyday usage of symbols in human communication systems (Ref 7). Just as traffic lights use an established code (green, yellow, red) to produce a desired outcome, for example, so too do histone modifications produce functionally-relevant outcomes in gene expression (Ref 7). In both cases there is a need for an ‘interpreter’ of the code. In the same way that a driver’s brain interprets traffic light signals, modification-dependent binding proteins interpret modified histones, effectively kick-starting processes such as cellular differentiation (Ref 7).
Whether all histone modifications are involved in defining gene expression patterns is currently a matter of deep debate (Ref 7). Moreover, there are numerous other epigenetic factors such as DNA methylation that influence which genes are actively transcribed (Ref 7). What is clear however is that the histone code provides the foundations for a sound, logical thread of reasoning that ultimately leads us to infer the activity of an intelligent agency. As Discovery Institute philosopher Stephen Meyer remarked:
“Our experience-based knowledge of information-flow confirms that systems with large amounts of specified complexity (especially codes and languages) invariably originate from an intelligent source – that is, from a mind or personal agent. Clearly, intelligent agents have the causal powers to generate novel linear information-rich sequences of characters. To quote Henry Quastler…the “creation of new information is habitually associated with conscious activity”. Experience teaches this obvious truth” (Ref 8).
It is with the acceptance of such a thread of reasoning that we can begin a more fruitful approach to understanding the molecular underpinnings of life.
1. Anthony Anumziato (2008), DNA Packaging: Nucleosomes And Chromatin, Nature Education (1), See http://www.nature.com/scitable/topicpage/DNA-Packaging-Nucleosomes-and-Chromatin-310
2. Chris Calladine & Horace Drew (1992), Understanding DNA: The Molecule And How It Works, 1st Edition, Academic Press, London, pp.138-143
3. Brian D. Strahl and C. David Allis (2000), The Language Of Covalent Histone Modifications, Nature, Vol 403, pp.41-45
4. ‘The Histone Code- Genetics, Epigenetics And Histones’, See http://www.histonecode.com
5. Adrienne Clements, Arienne N. Poux, Wan-Sheng Lo, Lorraine Pillus, Shelley L. Berger, Ronen Marmostein (2003), Structural Basis For Histone And Phophohistone Binding By The GCN5 Histone Acetyltransferase, Molecular Cell, Vol 12, pp.461-473
6. Raymond H Jacobson, Andreas G. Ladurner, David S. King, Robert Tjian (2000), Structure and Function of a Human TAFII250 Double Bromodomain Module, Science, Vol 288, pp.1422-1425
7. Bryan M Turner (2007), Defining An Epigenetic Code, Nature Cell Biology, Vol 9(1), pp.2-6
8. Stephen C. Meyer, Marcus Ross, Paul Nelson, and Paul Chien (2003), The Cambrian Explosion: Biology’s Big Bang, Appears in the peer-reviewed volume Darwinism, Design, and Public Education, Michigan State University Press p.381. See