Awakening lineage potential by Ikaros-mediated transcriptional priming

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.