Regulation of gene expression and the transcription factor cycle hypothesis.

Post-genomic data show unexpected extent of the transcribed genome and the size of individual primary transcripts. Hence, most cis-regulatory modules (CRMs) binding transcription factors (TFs) at promotor, enhancer and other sites are actually transcribed within full domain transcripts (FDTs). The ensemble of these CRMs placed way upstream of exon clusters, downstream and in intronic or intergenic positions represent a program of gene expression which has been formally analysed within the Gene and Genon concept [1,2]. This concept has emphasised the necessity to separate product information from regulative information to allow information-theoretic analysis of gene expression. Classically, TFs have been assumed to act at DNA level exclusively but evidence has accumulated indicating eventual post-transcriptional functions. The transcription factor cycle (TFC) hypothesis suggests the transfer of DNA-bound factors to nascent RNA. Exerting downstream functions in RNA processing and transport, these factors would be liberated by RNA processing and cycle back to the DNA maintaining active transcription. Sequestered on RNA in absence of processing they would constitute a negative feedback loop. The TFC concept may explain epigenetic regulation in mitosis and meiosis. In mitosis control factors may survive as single proteins but also attached to FDTs as organised complexes. This process might perpetuate in cell division conditioning of chromatin for transcription. As observed on lampbrush chromosomes formed in avian and amphibian oogenesis, in meiosis the genome is fully transcribed and oocytes conserve high Mr RNA of high sequence complexity. When new interphase chromosomes form in daughter cells and early embryogenesis, TFs and other factors attached to RNA might be reinserted onto the DNA.