ABSTRACT
Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment.
Subject(s)
DNA-Binding Proteins/metabolism , Hematopoietic Stem Cells/physiology , Megakaryocytes/physiology , Transcription Factors/metabolism , Animals , Cell Differentiation , DNA-Binding Proteins/genetics , Female , Gene Expression Profiling , Gene Expression Regulation , Hematopoietic Stem Cells/cytology , Lymphocytes/cytology , Lymphocytes/physiology , Male , Megakaryocytes/cytology , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , T-Lymphocytes/cytology , T-Lymphocytes/physiology , Transcription Factors/geneticsABSTRACT
Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFß function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFß activation, suggesting that Ikaros is an upstream negative regulator of the TGFß pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with γ-secretase inhibitors, which affects both TGFß-dependent and -independent pathways, but is Notch-independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity.
