Epigenetic programming of hematopoietic stem cells and their progeny.

The blood system produces more than ten mature cellular lineages all of which are derived from a small (1:10,000) pool of multi-potent, self-renewing hematopoietic stem cells (HSCs). Until recently, HSCs were thought to be a uniform cell population, and that the lineage commitment and differentiation of their progeny was determined by the stochastic action of lineage instructive transcription factors. However, it is now clear that distinct HSC populations exist which preferentially produce one subset of hematopoietic progenitors and differentiated cell types, but contribute little, or not at all, to other lineages.

We recently identified a HSC subpopulation with a strong platelet bias (Sanjuan-Pla et al., Nature 2013), and showed that these platelet-biased HSCs can give rise to HSCs with either myeloid or lymphoid lineage bias, but not vice-versa, suggesting that HSC populations are hierarchically organized, as are downstream, lineage-restricted progenitors.

We now wish to determine how these HSC subtypes are specified, and how their lineage bias is maintained. In particular, we want to understand how one type of lineage bias can replace another, and whether the epigenetic programme in biased HSC subtypes differ from those in the downstream lineage committed progenitors and their differentiating progeny.

To gain insight into these processes we will develop highly sensitive global profiling of the chromatin state of all cis-acting elements (e.g. enhancers, promoters and boundary elements) associated with platelet, myeloid and lymphoid lineage programs in pre-programmed HSCs and in the corresponding fully committed progenitors. This will allow the epigenetic profiles associated with bias and commitment to be directly compared. These studies will be combined with global RNA sequencing to identify putative mediators of the observed differences between chromatin states, including lincRNAs, transcription factors and chromatin modifications.