Genome-wide Lineage-Specific Transcriptional Networks Underscore Ikaros-Dependent Lymphoid Priming in Hematopoietic Stem Cells

Abstract

Summary Here we investigate the mechanisms that underlie the induction of developmental potential and establishment of cell fate during early hematopoiesis. A cascade of lineage-affiliated gene expression signatures, primed in hematopoietic stem cells (HSC) and differentially propagated in lineage-restricted progenitors, is identified. First evidence is provided for a stochastic sampling of lymphoid, erythroid and myeloid transcripts in HSC and multipotent progenitors (MPP). Multi-lineage priming is subsequently resolved upon lineage restrictions. Nonetheless, an unexpected association of lymphoid and myeloid signatures is detected past a nominal myeloid restriction point and a previously unappreciated lymphoid potential is revealed for this stage in development. New insight is provided into Ikaros' role as a bivalent regulator of multi-lineage priming during early hematopoiesis. Whereas Ikaros is responsible for activation of a cascade of lymphoid signatures in the HSC, at subsequent restriction points it is also involved in the repression of lineage-inappropriate signatures including stem cell-specific genes.

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

“…In line with its capacity for multilineage differentiation, the HSC compartment is transcriptionally primed for genes engaged in erythroid, myeloid, and lymphoid differentiation ( Fig. 2; Mansson et al 2007;Ng et al 2009;Guo et al 2013;van Galen et al 2014). Transcriptional priming is defined by low levels of gene expression that are not yet functional and is frequently associated with restricted but not silent chromatin and with activity of factors that function as pioneers in lineage differentiation (Bernstein et al 2006;Mikkelsen et al 2007;Zaret and Carroll 2011).…”

“…IKAROS is a key contributor to lymphoid lineage transcriptional priming in the HSC and its immediate progeny, the lympho-myeloid primed multipotent progenitor (LMPP) (Ng et al 2009). IKAROS-dependent transcriptional priming in the HSC and LMPP includes genes encoding membrane receptors and signaling factors such as the Il7r, Flt3, Cd79b, Notch1, Btla, Clnk, Ltb, and Ccr9, which are key regulators of early T-cell and B-cell differentiation (Fig.…”

“…This prevents extensive lymphoid progenitor self-renewal and association with cellular environments that support a cancer stem cell phenotype. In addition to its role in lymphoid lineage transcriptional priming, IKAROS is also engaged in the negative regulation of HSC-enriched genes (Ng et al 2009). Genes that belong to pathways that direct HSC interactions with a specialized niche, quiescence, and the ability to undergo self-renewing divisions are elevated in IKAROS-deficient HSCs and in downstream progenitors such as the LMPP and the granulocyte monocyte progenitor (GMP), where expression of these genes is normally extinguished (Ng et al 2009).…”

“…In stem cells, multipotent progenitors, and committed large pre-B cells there is a significant overlap in genes that are negatively regulated by IKAROS and belong to pathways that support cell-substrate adhesion and interactions with the microenvironment (Ng et al 2009;Joshi et al 2014). In contrast, the majority of IKAROS gene targets that are derepressed upon IKAROS loss in the HSCs and large pre-B cells remains unchanged in IKAROS-deficient DN and DP thymocytes ).…”

Transcription factor networks in dendritic cell development

“…The apparent mechanism by which Ikaros controls DC development is through its regulation of a large panel of receptors and transcription factors. Although classically considered to be required only for the priming of lymphoid lineages, gene expression analysis of the earliest cell stages of hematopoietic development revealed that the loss of Ikaros affects the expression of large gene sets associated with both lymphoid and myeloid lineages [73]. For example, the expression of Flt3, IL-7 receptor, Notch1, and the transcription factor Mef2c are all controlled by Ikaros, suggesting that it acts globally on many aspects of lineage specification [74].…”