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Developmental cues license emergency megakaryopoiesis in hematopoietic stem cells [scATAC-seq]

ABSTRACT: The fetal to adult switch in mouse hematopoietic stem cell (HSC) behavior is characterized by entry into quiescence and alterations in lineage output. Here we identify the ability of HSCs to undergo emergency megakaryopoiesis following acute inflammatory insult as an outcome of this developmental switch. Single cell accessibility mapping of fetal and adult HSCs resolves a heterogeneous chromatin landscape consistent with a two-step megakaryocyte lineage priming process. Importantly, we demonstrate that the accumulation of megakaryocyte primed HSCs is under the control of the developmentally restricted Lin28b RNA binding protein. Persistent Lin28b protein expression in postnatal HSCs delays the formation of a primed HSC pool and limits emergency megakaryopoiesis. Taken together, we identify Lin28b as a negative regulator of a megakaryocyte primed HSC state that is enforced at the chromatin level during unperturbed organismal development. These findings highlight the ontogenically timed onset of inflammatory responsiveness, with important implications for the delicate balance between host protection and tissue damage during neonatal life.

ORGANISM(S): Mus musculus

PROVIDER: GSE161724 | GEO | 2022/05/14

REPOSITORIES: GEO

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Project description:Hamey2017 - Blood stem cell regulatory network This model is described in the article: Reconstructing blood stem cell regulatory network models from single-cell molecular profiles Fiona K. Hamey, Sonia Nestorowa, Sarah J. Kinston, David G. Kent, Nicola K. Wilson, and Berthold Göttgens Proceedings of the National Academy of Sciences of the United States of America Abstract: Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks. As dysregulation of single HSC fate decisions is linked to fatal malignancies such as leukemia, it is important to understand how these decisions are controlled on a cell-by-cell basis. Here we developed and applied a network inference method, exploiting the ability to infer dynamic information from single-cell snapshot expression data based on expression profiles of 48 genes in 2,167 blood stem and progenitor cells. This approach allowed us to infer transcriptional regulatory network models that recapitulated differentiation of HSCs into progenitor cell types, focusing on trajectories toward megakaryocyte–erythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, we identified and subsequently experimentally validated a difference in the regulation of nuclear factor, erythroid 2 (Nfe2) and core-binding factor, runt domain, alpha subunit 2, translocated to, 3 homolog (Cbfa2t3h) by the transcription factor Gata2. Our approach confirms known aspects of hematopoiesis, provides hypotheses about regulation of HSC differentiation, and is widely applicable to other hierarchical biological systems to uncover regulatory relationships. This model is hosted on BioModels Database and identified by: MODEL1610060000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Developmental cues license emergency megakaryopoiesis in hematopoietic stem cells [scATAC-seq]

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