Aims
The long-term goal of the group is to define how chromatin modifying, transcriptional silencing complexes help control cell fate choices and lineage commitment during mammalian development.
Background
Cells of early mammalian embryos have the potential to develop into any adult cell type, and are thus said to be pluripotent. Pluripotency is gradually lost during embryogenesis as cells begin to commit to specific developmental pathways. While restriction of developmental potential is often associated with repression of inappropriate genetic programmes, a causal role for epigenetic silencing during early lineage commitment remains to be defined. My lab has found that Mbd3, a crucial and highly conserved component of the NuRD co-repressor complex, is necessary for gene silencing and maturation of pluripotent cells to a differentiation-competent state during early murine development, and for differentiation of ES cells (see figure below). This work has shed new light on a role for epigenetic silencing in the maintenance of pluripotent cells and in cell fate commitment during development.
Neurons and neural precursors from ES cells in culture Implanting embryo stained for trophectoderm (Eomes in green), pluripotent cells (Oct4 in blue) and primitive endoderm (Gata6 in red)
Approaches and Progress
We study pluripotent cells in early murine embryos, as well as embryonic stem cells. We are using a combined approach involving biochemistry, genetics, ES cell manipulation, in vitro differentiation, developmental biology, and gene expression analyses.
Lab members
Dominika Dudzinska, Anthony Hynes-Allen, Erin Knock, Paulina Latos, Donna Leaford, Patrick McDonal, Aoife O'Shaugnessy, Nicola Reynolds
References
Kaji K, Nichols J, and Hendrich BD (2007) Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells in mice. Development 134, 1123-1132 (Open access article)
Kaji K, Martin-Caballero I, MacLeod R, Nichols J, Wilson V and Hendrich B.(2006) The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nature Cell Biology 8, 285 - 292 Press Release; Going backstage
Prokhortchouk A, Sansom O, Selfridge J, Caballero I M, Salozhin S, Aithozhina D, Cerchietti L, Meng F G, Augenlicht L H, Maraidason J M, Hendrich B D, Melnick A, Prokhortchouk E and Bird A P. (2006) Kaiso-deficient mice show resistance to intestinal cancer. Molecular and Cellular Biology 26:199-208
Martín Caballero I and Hendrich B (2005) MeCP2 in neurons: closing in on the causes of Rett syndrome. Human Molecular Genetics 14:R19-R26