Grant: Operating Grant

Cells modulate expression of their genomes in response to different signals. For that, DNA must be transcribed to produce mRNAs that will be subsequently translated into proteins. This gene regulation takes place in the nucleus of cells where the DNA is packaged into a nucleoprotein structure called chromatin. Interestingly, this structure plays a major role in the regulation of genes. To activate or repress genes cells evolved very sophisticated mechanisms that deal with chromatin. Defects in these processes affect gene regulation, interfere with DNA replication, induce hyperrecombination and result in genome instability. Most of these defects are associated with tumorogenesis and cancer. We are specifically studying mechanisms of chromatin modulations associated with gene regulation. We have found factors that are dedicated to unfold chromatin structure, allowing access to DNA and therefore facilitating its transcription. Following transcription, these same factors repair the chromatin structure that has been unfolded, restoring the possibility of gene regulation. In this project we will focus on the role of a specific class of factors called histone chaperones. These proteins have the ability to assemble/disassemble chromatin during transcription. Interestingly, we discovered that histone chaperone activities modulate specific epigenetic marks. Epigenetic marks are generally modifications of chromatin that are not encoded in the DNA sequence but have a direct impact on gene regulation. We will use biochemical and yeast genetic approaches to understand the relationship between histone chaperones and epigenetic marks and how this interplay regulates genes. Given the importance of the mechanisms to be studied, the advances that we will make should lead to a better understanding of these basic and fundamental mechanisms in other eukaryotes, including humans. This could possibly lead to new innovative therapies to different diseases.