Awakening lineage potential by Ikaros-mediated transcriptional priming

Abstract

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.

Figure 1. Cascades of lineage-affiliated signatures directing early hematopoiesis

S-myly is the first in a series of lymphoid-myeloid lineage specific signatures that is primed in the HSC and propagated along the lymphoid and myeloid pathways. The rmyly is primed in the LMPP and marks restriction into a bi-potent lympho-myeloid state. The d-ly and d-my, are indicative of further restriction into the lymphoid or myeloid pathways. S-ery is the first of the erythoid lineage specific signatures that is primed in the HSC. The d-ery is primed after s-ery in committed megakaro-erythrocyte progenitors (MEPs) and demarcates commitment to the erythroid lineage. The stem signature is only expressed in the HSC and demarcates its properties such as self-renewal and multi-potency. Within the HSC, it is widely co-expressed with the s-myly and s-ery signatures. The stem signature is rapidly repressed in lineage-restricted progenitors that lack self-renewing potential.

Figure 2. Ikaros effects on priming of lymphoid lineage potential

A. Ikaros effects on the lymphoid and myeloid differentiation pathways. Ikaros is required for the generation of the CLP and ETP by priming lymphoid lineage-specific signatures in the HSC and LMPP. B. Ikaros activates an extensive lymphoid transcriptional program while it represses smaller cohorts of myeloid-, stem cell-and erythroid-specific genes in the HSC and LMPP. Key downstream targets of Ikaros that are positively (green arrow) or negatively (red block) regulated are shown in the diagram. Signature affiliation, gene function and sub-cellular localization of these genes also are indicated.