Grant: Foundation Grant

Acetyltranferases; Chromatin Immunoprecipitations; Chromosomal Translocations; Functional Genomics; Gene Regulation; Genome Maintenance And Stability; Histone Modifications; Histone Variants; Protein Complexes; Tumor Suppressors

<html> <body> <p>Using our continually evolving expertise, our research program is aimed at dissecting the molecular mechanisms of epigenetics, in which signals to chromatin mark different genomic loci and are read by effectors to translate a biological response. We efficiently use the power of biochemistry, yeast genetics, genome editing and "omics" to pursue our research program and develop parallel lines of studies in yeast and human cells. Our research program has been historically linked to the study of histone acetyltransferase complexes, namely those containing the MYST-family of enzymes and their co-factors of the ING family of tumor suppressors. We assembled a network of international collaborators who efficiently support our efforts to characterize these essential chromatin modifiers in nuclear functions, in order to understand how they regulate gene expression, as well as preserve genome integrity and perpetuation.<br> <br> Our research program has two broad goals:<br> <strong>1-Understanding gene regulation in chromatin and epigenetic phenomena.</strong> We will continue to decipher the epigenetic language through structural, functional and genomic characterization of protein modules present in transcription complexes that recognize specific histone marks during regulation of transcription. It will include the analysis of new histone modifiers discovered in the lab and the regulatory role of post-translational modifications on the complexes. An emphasis will be put on understanding the response to environmental stimuli and transmission of the gene transcription state, the basis of the epigenetic memory of a cell. Related to this, we will pursue work recently initiated to decode the molecular mechanism of genomic imprinting using the PWS locus, dissecting ncRNA interactions with chromatin modifiers. We will also pay specific attention to chromosomal translocations linked to different cancers which are presumed to merge histone modifier complexes together, in order to understand their oncogenic mechanism.<br> <br> <strong>2-Defining the pathways of genome maintenance in the context of chromatin.</strong> We will elucidate chromatin-based mechanisms to select and facilitate repair pathways at DNA lesions. Recent work suggests that signaling to histones regulates association of effector proteins that control selection of DNA repair factors. Newly identified interactions of histone modifiers with key repair proteins will be studied in depth, as most DNA repair factors are found acetylated in vivo, which can regulate their function. In parallel, we will also continue to study chromatin dynamics during genome duplication, with an emphasis on the advancing replication fork instead of the origins.<br> <br> The research team will continue to include several graduate students and post-doctoral fellows, supported by research assistants dedicated to yeast and human systems. The trainees will get experience in state-of-the-art technologies, including genome editing and analysis of interactions/locations in physiological conditions. They will participate in stimulating multidisciplinary academic activities and high profile international scientific meetings in the field.<br> <br> Our future work will provide critical new information as well as identify new players that control genome expression and maintenance. The findings will have high scientific impact and will produce new targets for cancer prevention/treatment, as epigenetic-based therapy and epi-mutations have become most promising for cancer research.</p> </body> </html>