Wednesday, 19 August 2009

Role of polycomb and trithorax in developmental regulation

During development, patterns of differential gene expression, defining determined state of cells, needs to be maintained over several generations. A set of genes called polycomb and trithorax group genes (PcG and trxG) respectively have been identified in Drosophila which seem to exert such a memory function. In Drosophila, the earliest development is controlled by the expression of maternal genes while the final segment specificty is governed by the master regulator homeobox (Hox) genes. The hox genes encode various transcription factors which regulate many downstream genes. These factors have to be expressed in appropriate patterns during development. The expression of Hox genes, is regulated initially by activators and repressors encoded by the gap and pair ruled genes. These factors however, have a very short half life and hence decay once the Hox gene expression is initialized. It is during this period, that the PcG and trxG proteins recognize the transcriptionally repressed and active states (respectively) of the Hox genes and maintain their expression throughout development.
The polycomb and trithorax genes therefore seem to be acting antagonistically. Polycomb genes are involved in chromatin based gene silencing while trithorax group genes counteract this silencing effect to maintain gene activity. Also since they maintain the Hox gene expression throughout the process of development they may serve as molecular memory systems central to the process of development.
The exact mechanism by which these genes act is still not clear. However a pathway has been proposed which recruits these genes to their target sites on the DNA called Polycomb and Trithorax Response Elements(PREs and TREs). Once at their sites they regulate transcription by modulating the chromatin structure, in particular, via post translational modification of histones and by regulating the three dimensional organization of the TREs and PREs.
Various questions, as to the exact mechanism by which the PcG genes initially recognize the repressed state of their target genes (Hox) remain unanswered as of now. Also how these genes maintain this silenced state of chromatin and transmit the same through many cycles of cell division is intriguing too.

In the next post we shall look at the post translational histone modifications that happen once these proteins reach their target sites on the DNA.