Developmental Epigenetics: from signalling to transcription

Ras and Notch signalling pathways are involved in a plethora of basic biological processes such as proliferation, differentiation, and apoptosis. Even though the core components of these pathways are now identified, the mechanisms of modulation essential to generate an appropriate level of signalling remain poorly defined.

In the past few years my laboratory has performed numerous RNAi screens in divers sensitive backgrounds and a theme has emerged: chromatin organisation is crucial for appropriate attenuation of the RAS signalling pathway. Indeed, we have uncovered the MLL complex (Wang et al., Dev Biol 2011, and Fisher et al., Dev Biol, 2010,), and a bromodomain containing protein BET-1 (Gee et al., manuscript in preparation). Depletion of any of these proteins can cause hyperactivation of the RAS signalling pathway and affect cell fate adoption during development. We also have other candidate genes awaiting further characterisation. See Poulin Lab Website for more information.

The embryo generates two types of cells: somatic cells, which are destined to die, and germ cells, which ensure immortality of the species. These two types of cells are very different. For example, a muscle is a somatic cell, it has a very specialised function and its genetic material will not be passed on to the next generation. On the other hand, the genetic material of germ cells will be inherited. But how can the embryo generate these two strikingly different types of cells? One theory being explored is that the embryo sets aside precursor cells that will not differentiate into somatic cells, but instead maintain totipotency. Totipotency is acquired when a cell can self-renew and retains the capacity to generate any cell of an organism. We now know that chromatin plays an important role in this. Chromatin is made of the genetic material, DNA, wrapped around protein structures called nucleosomes. Interestingly, nucleosomes are ‘decorated’ with chemical modifications, and these give special properties to the genetic material. Cancer cells exploit these modifications to self-renew indefinitely. Thus, at a fundamental level, our research may impact on cancer research.