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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.

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