Haemopoiesis: Study of the molecular mechanisms and dynamics of cell differentiation
One of the great challenges for future biological research will be to understand in a system-wide fashion how cell fate decisions are regulated. Great progress has been made with respect to identifying individual components of the cell fate decision machinery, such as transcription factors (TFs), chromatin components and signalling components. However, while recent genome-wide studies allow a first glimpse into the complexities of TF-DNA interactions in specific cell types, we know very little about hierarchical relationships between different network states or how metastable states are established and eventually altered. We also do not know how specific chromatin structures influence the dynamics of TF accessibility. Or, in other words, how the ordered interplay of TFs and specific chromatin states eventually leads to the stable expression of lineage specific genetic programs. This proposal will use haemopoiesis as a model to identify the molecular mechanisms and dynamics of cell differentiation in a system-wide fashion. To this end we have formed a consortium consisting of experimental researchers and computational biologists to make use of hemopoietic development as particularly powerful system for the reconstruction of dynamic and global models of the molecular interactions governing an entire developmental pathway.
Our consortium will share the huge task of identifying the dynamics of TF assembly during development in a genome-wide fashion, to perform parallel experiments examining global DNA methylation and chromatin alterations, to obtain mechanistic insights by manipulating the trans-regulatory environment and to verify conclusions by examining specific classes of genes in more detail.
1) What is the molecular basis of the hierarchical action of key regulators of haematopoiesis?
2) How are known key regulators integrated into wider transcriptional networks with a particular emphasis on the dynamical nature of network transitions through sequential regulatory states?
3) How do these TFs interact with the chromatin template and how do they regulate chromatin accessibility and chromatin modification?
4) Can we decipher the genomic regulatory blueprint for development of a mammalian organ system?
Funding InformationLong and Larger Grant, Biotechnology and Biological Sciences Research Council (BBSRC)