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Critical modulation of hematopoietic lineage fate by Hepatic Leukemia Factor

ABSTRACT: A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor Hepatic Leukemia Factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its’ normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf-binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid and ablation of lymphoid gene programs, with Hlf induction of Nuclear Factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE69858 | GEO | 2016/06/12

SECONDARY ACCESSION(S): PRJNA286986

REPOSITORIES: GEO

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Critical modulation of hematopoietic lineage fate by Hepatic Leukemia Factor

Project description:Hematopoiesis commences with a gradual restriction in lineage potential of multipotent stem/progenitor cells, but the underlying molecular events of this remain incompletely understood. We here identify robust expression of the transcription factor Hepatic Leukemia Factor (Hlf) in multipotent hematopoietic progenitors, which is rapidly lost with differentiation. Prolonged Hlf expression reveals it as a strong negative regulator of lymphoid development and results in a pronounced and reversible differentiation block in the B-cell lineage, while remaining compatible with myeloid fates. Reciprocally, we observe rapid lymphoid commitment upon eduction of Hlf activity. These phenotypes result from Hlf-binding to active enhancers of myeloid-competent cells, induction of myeloid-affiliated transcription and ablation of lymphoid gene programs, with Hlf induction of Nuclear Factor I C (Nfic) as a functionally relevant target gene. Collectively, we establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage restricted progeny.

2018-10-30 | GSE106555 | GEO

Critical modulation of hematopoietic lineage fate by the PAR/bZIP transcription factor Hepatic Leukemia Factor

Project description:Blood cell formation is a tightly regulated process initiated from a rare population of multipotent hematopoietic stem cells. Subsequent differentiation proceeds in a hierarchical manner with the generation of intermediate progenitor cells, in which alternative lineage potentials become gradually restricted. A deeper understanding of these events is crucial not only to understand normal blood cell formation, but also for leukemia, where a defining feature is inappropriate differentiation. Here, we identified Hepatic Leukemia Factor (Hlf) as being highly and selectively expressed in primitive multipotent hematopoietic stem and progenitors. We demonstrate that Hlf is a strong negative regulator of B-, NK- and T cell development and instructs multipotent progenitors to adopt a myeloid fate in a cell autonomous manner; phenotypes underwritten by the induction of myeloid affiliated transcriptional programs, the concomitant ablation of lymphoid gene programs and a genome-wide binding spectra that involved active enhancers of myeloid-competent cells. Collectively, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis. Gene expression profiling of control or Hlf/Hlf lentivirus infected GMLPs (2 replicates per group) and Hlf inducible GMLPs maintained for 4 days on OP9 stroma in the presence or absence of doxycycline (2 replicates per group)

2016-06-12 | E-GEOD-69858 | biostudies-arrayexpress

Critical modulation of hematopoietic lineage fate by the PAR/bZIP transcription factor Hepatic Leukemia Factor

Project description:Blood cell formation is a tightly regulated process initiated from a rare population of multipotent hematopoietic stem cells. Subsequent differentiation proceeds in a hierarchical manner with the generation of intermediate progenitor cells, in which alternative lineage potentials become gradually restricted. A deeper understanding of these events is crucial not only to understand normal blood cell formation, but also for leukemia, where a defining feature is inappropriate differentiation. Here, we identified Hepatic Leukemia Factor (Hlf) as being highly and selectively expressed in primitive multipotent hematopoietic stem and progenitors. We demonstrate that Hlf is a strong negative regulator of B-, NK- and T cell development and instructs multipotent progenitors to adopt a myeloid fate in a cell autonomous manner; phenotypes underwritten by the induction of myeloid affiliated transcriptional programs, the concomitant ablation of lymphoid gene programs and genome-wide binding spectra that involved active enhancers of myeloid-competent cells. Collectively, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

2016-07-11 | GSE69817 | GEO

A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors [ChIP-seq]

Project description:The commitment of hematopoietic stem cells and multipotent progenitors (MPPs) can be tuned to reprogram their differentiation capacity to be biased toward myeloid cells in response to an infection. Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, repressed a cohort of genes of myeloid function (myeloid genes) and activated those for lymphoid function (lymphoid genes) in MPPs. In addition, Bach2 repressed both Cebpb and its target Csf1, encoding C/EBPβ and macrophage colony-stimulating factor (M-CSF), respectively, whereas C/EBPβ repressed Bach2 and activated the M-CSF receptor gene Csf1r. Bach2 and C/EBPβ bound to overlapping regulatory regions of their myeloid target genes, suggesting the presence of a gene regulatory network (GRN) with mutual repression and antagonistic, feed-forward regulation of myeloid genes. Lipopolysaccharide reduced the expression of Bach2, resulting in enhanced myeloid differentiation. Bach2 tunes the commitment of multipotent progenitors to myeloid and lymphoid lineages under both normal and infectious conditions.

2017-03-13 | GSE87503 | GEO

IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors

Project description:This SuperSeries is composed of the following subset Series: GSE34892: IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Affymetrix). GSE34915: IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Illumina). Refer to individual Series

2012-01-07 | E-GEOD-34917 | biostudies-arrayexpress

A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors [expression]

Project description:Hematopoietic stem cells and multipotent progenitors (MPPs) commitment can be tuned in response to an infection so that their differentiation is biased toward myeloid cells. Here we find that Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, represses a cohort of myeloid genes and activates those linked to lymphoid function. Bach2 repressed both Cebpb and its target Csf1r, encoding C/EBPβ and macrophage colony-stimulating factor receptor (M-CSFr), respectively, whereas C/EBPβ repressed Bach2 and activated Csf1r. Bach2 and C/EBPβ further bound to overlapping regulatory regions at their myeloid target genes, suggesting the presence of a gene regulatory network (GRN) with mutual repression and antagonistic, feed-forward myeloid gene regulations. Lipopolysaccharide reduced the expression of Bach2, resulting in enhanced myeloid differentiation. The Bach2-C/EBPβ GRN pathway thus tunes MPP commitment to myeloid and lymphoid lineages under both normal conditions and after infection.

2017-03-07 | GSE80954 | GEO

Clonal barcoding of endogenous adult hematopoietic stem cells reveals a spectrum of lineage contributions

Project description:The hierarchical model of hematopoiesis posits that self-renewing, multipotent hematopoietic stem cells (HSCs) give rise to all blood cell lineages. While this model accounts for hematopoiesis in transplant settings, its applicability to steady-state hematopoiesis remains to be clarified. Here we used inducible clonal DNA barcoding of endogenous adult HSCs to trace their contribution to major hematopoietic cell lineages in unmanipulated animals. Whereas the majority of barcodes were unique to a single lineage, we also observed frequent barcode sharing between multiple lineages, specifically between lymphocytes and myeloid cells. These results suggest a spectrum of multipotent and unipotent HSCs that collectively drive continuous hematopoiesis in the adult, and highlight a close relationship of myeloid and lymphoid development.

2024-01-05 | GSE246271 | GEO

Stromal STAT5-mediated trophic activity regulates hematopoietic multipotent progenitor niche factors

Project description:Signal transducer and activator of transcription 5 (STAT5a and STAT5b) are intrinsically critical for normal hematopoiesis but are also expressed in stromal cells. However, hematopoiesis-supporting stromal function has not been reported. Here, STAT5ab knockout (KO) was generated with a variety of bone marrow hematopoietic and stromal Cre transgenic mouse strains. Pan-hematopoietic deletion with Vav1-Cre was the positive control for loss of multipotent hematopoietic function but surprisingly dysregulated niche factor mRNA expression and deleted STAT5ab in CD45neg cells. Single cell transcriptome analysis of mouse bone marrow from wild-type or Vav1-Cre KO mice showed major changes in hematopoietic stem cell myeloid commitment genes and upregulated protein translation genes throughout myeloid-primed clusters.

2023-10-01 | GSE214857 | GEO

A revised map of the human progenitor hierarchy reveals origin of macrophages and dendritic cells in early lymphoid development

Project description:The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision. The validity of this model has recently been questioned in the mouse, however little is known concerning lineage potential of human progenitors. Here we provide a comprehensive analysis of the human hematopoietic hierarchy by clonally mapping the developmental potential of 7 progenitor classes from neonatal cord blood and adult bone marrow. Human multi-lymphoid progenitors, identified as a distinct population of Thy1-/loCD45RA+ cells within the CD34+CD38- stem cell compartment, gave rise to all lymphoid cell types, as well as monocytes, macrophages, and dendritic cells, indicating that these myeloid lineages arise in early lymphoid lineage specification. Thus, as in the mouse, human hematopoiesis does not follow a rigid model of myeloid-lymphoid segregation. Total RNA was extracted from 5 - 10,000 sorted cord blood progenitor cells to compare gene expression

2010-06-23 | E-GEOD-21973 | biostudies-arrayexpress

Hepatic Leukemia Factor maintains quiescence of hematopoietic stem cells and protects the stem cell pool during regeneration

Project description:The transcription factor hepatic leukemia factor (HLF) is highly expressed in hematopoietic stem cells (HSCs) and has been proposed to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function has remained unknown. Here we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters. By contrast, when challenged through transplantation, Hlf deficient HSCs demonstrate an impaired ability to reconstitute hematopoiesis and gradually exhaust upon serial transplantation. Transcriptional profiling displayed changes associated with cellular activation in Hlf deficient HSCs, and cell cycle analysis showed a significant reduction of dormant HSCs. Accordingly, Hlf deficient mice were hypersensitive to toxic insults targeting dividing cells that completely eradicated the HSC pool. In summary, our findings unravel a novel role for HLF as a critical regulator of HSC quiescence and as an essential factor to maintain the HSC pool during regeneration.

2017-12-18 | GSE100385 | GEO

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