Bertrand Joseph: Life and Death Decisions at the Cellular level

Although neoplasia involves many other processes, in almost all instances, deregulated cell proliferation and suppressed cell death together provide the underlying platform for neoplastic progression. Cell proliferation and apoptotic cell death can be defined by a unique set of molecular events. However, they are not disconnected; they rather function as an integrated molecular network. Our group investigates the interconnections between these processes and focuses its research on the genetic and epigenetic regulation of this molecular network.

How one and the same gene can regulate cell life and death

We aim to define how one and the same gene, depending of the cell context, can interfere with the signaling pathways regulating both cell life and death. In fact, multifunctional proteins are comparable to "Swiss army knife" with different blades/domains exerting their different effects.

Reprogramming cancer cells to die.

We also examine whether, using small molecules targeting histone tail modifying enzymes, one can reprogram cancer cells to die. Investigation of histone modifications in the regulation of gene expression has grown exponentially. However, histone modifications are not only essential for appropriate activation and repression of transcription, but are also strongly influencing elongation and higher chromatin order structure which could influence tumor cells response to death stimuli. Major players in this regulation are the histone acetyltransferases (HAT), which acetylate the histone tails and induce chromatin decondensation, histone deacetylases (HDAC), which remove the acetyl groups and promote a tighter binding of histones to DNA, histone methyltransferases (HMT) which promotes or inhibits transcription depending on the target histone residue and histone demethylases (HDM) which counteracts the HMTs. Growing evidence suggest that all of these proteins are found deregulated in human cancers. We investigate the role for control of histone tail acetylation/methylation by HAT/HDAC/HMT/HDM in regulation of higher chromatin order structure and programmed cell death and how the deregulation of this interplay contributes to resistance of tumor to treatments.