A holistic model of the genome and the genon concept of regulation

Systems biology exploits networks implying virtual and physical interactions of macromolecules. In a cell, significant interactions are plethoric and may never allow projection of a comprehensive model. This holds true for DNA- and RNA-protein interactions controlling gene expression: if there are up to 500.000 proteins (encoded in 20-30.000 genomic domains), as many mRNAs must be controlled in the cellular space and in time. To simplify matters, one might single out specific control networks at individual levels of the Cascade of Regulation (1), excluding NA-interactions with cellular structure (e.g. nuclear matrix, cytoskeleton), or other identifiable secondary networks. The Genon concept (2) allows identification of specific cis-programs at DNA and RNA level controlling gene expression under the influence of trans-acting factors. The basic unit-program is the cis-genon an ensemble of signals added and super-imposed onto the coding sequence of an mRNA, forming an mRNA-protein complex (mRNP) under the influence of factors from the transgenon. Systematically going through all levels of genomic and cellular organisation from the DNA down to individual proteins a Holistic Model of genome and gene expression may be proposed. - Surprisingly, one of the simplest pertinent networks that might be analysed is constituted by the genome itself. The - largely forgotten - phenomenon of ectopic pairing shows that DNA is organised into a 3D network (cf. 3). Indeed, in the light microscope cables can be observed, at interband level, between the 4 polytene chromosomes of Drosophila which link specific genomic domains with each other: this network holds every part of the genome in a specific 3D position. It was established by 1948 that these cables are heritable and hence genetically determined. Recent data imply that such inter-chromosomal links are present in normal cells as well and important in gene regulation. According to actual genomics data, the 4 drosophila chromosomes are subdivided into about 5000 observable bands, representing genomic domains as units of transcription and meiotic recombination. About 200 ectopic cables can be directly observed and mapped; for the entire fly genome we may thus assume the actual number to about 500 ectopic cables. In analogy, the human genome might thus contain about 2500 such links, assuming 25.000 genomic domains divided among the 46 chromosomes. It is obvious that this network must be based on accessible euchromatin. Since the organisation of hetero- versus euchromatin changes in cell differentiation, this 3D network must be variable, most likely controlled by trans-acting factors acting at DNA/chromatin level. This might thus provide a greatly simplified model to apply systems biology and information theoretic analysis at DNA level, the first step that controls gene expression. - Within the Holistic model one might expand this analysis to downstream levels of regulation: (1) the DNP networks of chromatin organisation of individual genomic domains controlled by the protogenon (cf. 2), (2) the 3D pattern of pre-mRNAs at individual steps of processing, conditioned by their pre-genon and pre-transgenon, down to (3) the 3D structure of an mRNA forming an mRNP complex by interaction of factors from the transgenon with its individual genon. These mRNPs, in turn, are basic elements of the entire network of the ensemble of mRNPs operating in a cell under the influence of trans-acting factors. Possibly, the systems approach may allow one day to integrate all these networks and make feasible their analysis by information theory.

(1) Klaus Scherrer (1980) In Kolodny (ed.), Eukaryotic Gene Regulation. CRC press Inc., Boca Raton, Florida, Vol. 1, pp. 57-129.
(2) Klaus Scherrer and Jürgen Jost (2007) Mol Syst Biol. 3:87. Epub 2007 Mar 13. (EMBO and Nature Publishing Group.), (doi:10.1038/msb4100123)

(3) Scherrer, K. (1989) Bioscience Reports, 9, 157-188