Flexibility of the transcription regulatory code

Kel A.E., Ratner V.A.

kel@bionet.nsc.ru

 

“Fuzzy puzzle” – flexible coding of multiple regulatory messages in the same DNA sequence

The multiplicity of the cellular conditions in which eukaryotic genes are to be expressed gives rise to the polyfunctionality of the structure of their transcription regulatory regions.

We present a “fuzzy puzzle” hypothesis of coding multiple regulatory messages in the same DNA sequence in the regulatory regions of eukaryotic genes. The structure of regulatory sequences on one hand and the specific features of transcription factors on the other hand provide a possibility to encode several regulatory programs within one regulatory region (see Fig. 1). It is known that each transcription factor has the ability to bind to a variety of different DNA sites. This is maintained by flexible mechanisms of DNA-protein interactions, when DNA conformation rather than the particular sequence context often the major role in selection of DNA targets. In addition, the ability of TFs to operate through a so-called “induced fit” mechanism (when a TF becomes finally structured only upon interaction with DNA; Frankel and Kim, 1991) greatly relaxes the restrictions from binding to various DNA sites. Besides that, the protein-protein interactions between different transcription factors in the multiprotein regulatory complex become very important. Protein-protein interactions could stabilize some low-energy protein-DNA contacts thus additionally widen the variety of target sites for particular transcription factors. The huge diversity of transcription factors functioning in the living cells multiplied by the wide choice of target sites for each TF give rise to a precondition to form multiple alternative DNA-protein complexes on the same gene regulatory region. As a result extremely complex patterns of gene expression are observed.

Figure 1. Fuzzy puzzle hypothesis of the multipurpose structure of the eukaryotic promoters: of coding multiple regulatory messages in the same DNA sequence. A,B,C and D,E,F – two sets of TF; 1,2 – two sites in DNA; BC – basal complex.

 

The “fuzzy puzzle” coding breaks off the evolutional limitations on multicellular organisation.

“Fuzzy puzzle” principle of coding is the result of genome evolution of the multicellular organisms on the way of breaking the evolutional limitations caused by the requirement of multiple ontogenetic programs to be encrypted in a single genome.

We believe that the coding of regulatory information on the base of “fuzzy puzzle” principle has developed as a consecutive phase of the progressive evolution during occurrence of multicellular organisms. A number of the most important phases in the scheme of biological evolution of genomes could be outlined (Ratner, 1995). These phases correspond to the moments of obtaining some new principle features of wide profile that break off some evolutional limitations (see Fig. 2). One of such phase was the origin of diploidity that breaks off the limitation on genome length caused by the “error catastrophe”. The next phase was the obtaining of chromatin that breaks off the limitation on duplications as an evolutional reserve. This limitation was caused by instability of procaryotic genomes in respect to repeats (Kel et al., 1991). We think that grows of complexity of multicellular organisms, appearance of huge verity of different cell types, emergence of exclusively complex development programs require very complex gene regulation mechanisms. Simple procaryotic mechanism of transcription regulation based on few regulatory proteins very specific to their target sequences and working in narrow and very particular cellular situations was not able to provide the required complexity. It cased the limitation on coding potential of regulatory sequences. The required solution was the “fuzzy puzzle” coding of multiple messages in regulatory regions of eukaryotic genes. The following features of transcription factors and their sites in DNA provide development of such coding principle:
1. Decrease of binding specificity.

2. Induced fitting

3. Protein-protein interactions between transcription factors.

All these features provide possibility to form alternative transcription regulatory complexes on one regulatory sequence depending on the presence in the cell corresponding transcription factors and the order of their binding to DNA sites.

Figure 2. Stepwise breaking off evolutional limitations in the course of progressive evolution to multicellular eukaryotic organisms.

 

The “fuzzy puzzle”coding is the basis for a new, very effective mechanism of evolution

We believe that the flexibility of transcription regulatory code based on the “fuzzy puzzle” principle ones appeared in evolution becomes a keystone for a new highly effective mechanism of evolution of multicellar organisms. The huge verity of transcription factors functioning in every cell that have possibility to bind a diversity of DNA sites widen significantly the range of possible regulatory sequences. Origination of new sequences that regulate gene transcription (promoters, enchancers) does not require a long time for sorting out, since practically every DNA sequence become able to furnish the regulatory function. (see. Fig. 3). Under such conditions an extremely fast evolution of regulatory regions may be maintained. Indeed, particular exiting is the high verity of eukaryotic promoters that is the result of intensive evolution of gene regulation on the last steps of eukaryotic evolution.

Figure 3. Three mechanisms of evolution of biopolymers.