Person:

Ng, Samuel

Bioinformatic studies on a revised hierarchy of hematopoietic progenitors have provided a genome-wide view of lineage-affiliated transcriptional programs directing early hematopoiesis. Unexpectedly, lymphoid, myeloid, and erythroid gene expression programs were primed with similar frequency at the multipotent progenitor stage indicating a stochastic nature to this process. Multilineage transcriptional priming is quickly resolved upon erythroid lineage restriction with both lymphoid and myeloid transcriptional programs rapidly extinguished. However, expression of lymphoid and myeloid factors remains active past nominal lymphoid and myeloid lineage restrictions, revealing a common genetic network utilized by both pathways. Priming and resolution of multilineage potential is dependent on the activity of the DNA binding factor Ikaros. Ikaros primes the lymphoid transcriptional program in the HSC and represses the stem cell and other disparate transcriptional programs downstream of the HSC. Loss of Ikaros removes the lymphoid leg of the immune system and may confer aberrant self-renewing properties to myeloid progenitors.

The mechanisms regulating lineage potential during early hematopoiesis were investigated. First, a cascade of lineage-affiliated gene expression signatures, primed in hematopoietic stem cells (HSCs) and differentially propagated in lineage-restricted progenitors, was identified. Lymphoid transcripts were primed as early as the HSC, together with myeloid and erythroid transcripts. Although this multilineage priming was resolved upon subsequent lineage restrictions, an unexpected cosegregation of lymphoid and myeloid gene expression and potential past a nominal myeloid restriction point was identified. Finally, we demonstrated that whereas the zinc finger DNA-binding factor Ikaros was required for induction of lymphoid lineage priming in the HSC, it was also necessary for repression of genetic programs compatible with self-renewal and multipotency downstream of the HSC. Taken together, our studies provide new insight into the priming and restriction of lineage potentials during early hematopoiesis and identify Ikaros as a key bivalent regulator of this process.

The ability of somatic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that keep stem cell-specific genes active and key differentiation factors repressed but poised for activation. The epigenetic factors that provide this type of regulation remain ill-defined. Here we provide the first evidence that the SNF2-like ATPase Mi-2beta of the Nucleosome Remodeling Deacetylase (NuRD) complex is required for maintenance of and multilineage differentiation in the early hematopoietic hierarchy. Shortly after conditional inactivation of Mi-2beta, there is an increase in cycling and a decrease in quiescence in an HSC (hematopoietic stem cell)-enriched bone marrow population. These cycling mutant cells readily differentiate into the erythroid lineage but not into the myeloid and lymphoid lineages. Together, these effects result in an initial expansion of mutant HSC and erythroid progenitors that are later depleted as more differentiated proerythroblasts accumulate at hematopoietic sites exhibiting features of erythroid leukemia. Examination of gene expression in the mutant HSC reveals changes in the expression of genes associated with self-renewal and lineage priming and a pivotal role of Mi-2beta in their regulation. Thus, Mi-2beta provides the hematopoietic system with immune cell capabilities as well as with an extensive regenerative capacity.