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High-throughput single cell gene expression analysis in primary blood stem and progenitor cells identifies new links between key transcriptional regulators

ABSTRACT: Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors (TFs) in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterised by distinctive TF expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated TF pairings, including previously unrecognised relationships between Gata2, Gfi1 and Gfi1b. Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a novel regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between Gfi1 and Gfi1b. Single cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE42518 | GEO | 2013/04/24

SECONDARY ACCESSION(S): PRJNA182188

REPOSITORIES: GEO

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High-throughput single cell gene expression analysis in primary blood stem and progenitor cells identifies new links between key transcriptional regulators

Project description:Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors (TFs) in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterised by distinctive TF expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated TF pairings, including previously unrecognised relationships between Gata2, Gfi1 and Gfi1b. Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a novel regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between Gfi1 and Gfi1b. Single cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease. Examination of Gata2 and Gfi1 binding patterns in murine mast cells

2013-04-24 | E-GEOD-42518 | biostudies-arrayexpress

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Project description:We used the paradigmatic 'GATA-PU.1 axis’ to explore, at systems-level, dynamic relationships between transcription factor (TF) binding and global gene expression programs as multipotent cells differentiate. We combined global ChIPSeq of GATA1, GATA2 and PU.1 with expression profiling during differentiation to erythroid and neutrophil lineages. Our analysis reveals (i) differential complexity of sequence motifs bound by GATA1, GATA2 and PU.1; (ii) the scope and interplay of the GATA1 and GATA2 programs within, and during transitions between, different cell compartments, and the extent of their hard-wiring by DNA motifs; (iii) the potential to predict gene expression trajectories based on global associations between TF-binding data and target gene expression and (iv) how dynamic modeling of DNA-binding and gene expression data can be used to infer regulatory logic of TF circuitry. This 'rubric' exemplifies the utility of this cross-platform resource for deconvoluting the complexity of transcriptional programs controlling stem/progenitor cell fate in hematopoiesis. We examine binding of three factors Gata1, Gata2 and Pu1 at 3 stages of differentiation (multipotential, 5 days of erytroid and neutrophil) , while looking at 2 intermeditate stages of erythroid differentiation for factors Gata2 and Gata1. We also look at Gata2 and Gata1 binding after Gata1 induction using an ER fusion protein.

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