• Home
• Project
• Epigenetic Flip Flop
• Background

Background

Cell differentiation and environmental adaptation depends on external and internal perturbations, as a response of cellular behavior for survival or linage trade-offs. This adaptation is attained by several robust cellular networks, which are based on expression or repression of the appropriate genes. (Bühler & Gasser, 2009; Huang, 2003) In yeast there exist two main inhibitory mechanisms to regulate gene expression, activation/repression of specific promoters and gene silencing. Both mechanisms are based on similar molecular mechanisms, which involve binding of eukaryotic factors to the DNA, and the recruitment of enzymes and structural proteins that modify promoter activity that eventually result in the execution of a particular expression program. Compaction of chromatin and the consequent heterocromatin formation are usually mediated by silencing proteins and proteins-recruiting DNA sequences, that can interact over long distances. Silencing has an important role in yeast, for example, in mating type, lineage specification, centrosome silencing and compact telomeres structure. (Ratna et al, 2009; Bühler & Gasser, 2009; Huang, 2003)

Beyond the deciphering of the Human Genome, epigenetics has become one of the new challenges of the 21st century. However, because of the complexity of the epigenetic code, there is still a lot to discover before it could be completely understood. Even though little is know about the regulation of the heritability between generations, it is a fact that there exist huge and intriguing networks that coordinate the activation and inactivation of gene expression, and also the maintenance of cell identity. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. Nevertheless, some of the patterns that govern the switch between on and off of certain genes by chromatin remodeling have seen the light, allowing something new to start.

Epigenetics, as it has been demonstrated in cellular reprogramming, has opened a new era in our understanding of life and it is a new precious tool that will contribute to improve the treatment of many human diseases.

In previous works, there were used heterologous synthetic gene expression systems to demonstrate that spatial distribution of activators and repressors binding sites influences gene expression resulting in monostable or bistable regulation of a promoter. (Kelemen et al, 2010; Kramer et al, 2004) It has been demonstrated that if repressors bind both downstream and upstream of the coding sequence, the response is bistable, but if they bind only to one site, the response become monostable. (Kelemen et al, 2010; Ratna et al, 2009) It has also been studied the behavior of repressors when they bind to specific sites and spread their inhibitory effect along the DNA.(Sedighi, 2008)

Figure 1. (A) The steps involved in the reaction–diffusion model (from top to bottom): nucleation, autocatalytic recruitment, and nonlinear diffusion. (B) Evolution of the simulated concentration distributions of silencing proteins along a DNA segment nucleated at two sites. The internucleation distance was 1.2 kb.(Kelemen et al, 2010)

In eukaryotic genomes, specific genes promoters are flanked by silencer sequences in a chromosomal region that control their expression. It has been observed that repression is distance and position dependent. Distance between upstream and downstream operator sites also regulate promoter activity. Moreover, heterochromatin context of genes, as those located near to centromeres and telomeres, seems to be important in gene silencing. (Ratna et al, 2009)