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Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells [RNA-seq]

ABSTRACT: Blood production is maintained through adult life by haematopoietic stem cells which undergo a process of differentiation and increasing lineage restriction to produce all the terminal blood types. The cell type transitions within this process are tightly controlled, and loss of control can lead to inappropriate proliferation and leukemic transformation. We and others have previously described seven transcriptional regulators (heptad; LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) which bind key haematopoietic genes in normal human CD34+ haematopoietic stem and progenitor cells (HSPCs). Heptad factors form a densely interconnected circuit by binding combinatorically at their own, and each other’s, regulatory elements. However, the precise role of the heptad throughout normal and leukemic haematopoiesis, including whether all seven factors act together in single cells, and whether heptad perturbation can influence cell fate decisions remain unclear. In this study we integrate bulk and single cell data in normal human HSPCs and leukemic cells and find that chromatin conformation at key heptad regulatory elements is predictive of cell identity in normal and leukemic progenitors. The interconnected heptad circuit identified in normal HSPCs persists in AML, but single cell transcriptomics suggest that specific heptad sub-circuits exist in individual cells, and we show that GATA2, TAL1 and ERG play key roles in regulating the stem to erythroid transition in both normal and leukemic contexts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158795 | GEO | 2021/05/27

REPOSITORIES: GEO

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Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells [scRNA-seq]

Project description:Blood production is maintained through adult life by haematopoietic stem cells which undergo a process of differentiation and increasing lineage restriction to produce all the terminal blood types. The cell type transitions within this process are tightly controlled, and loss of control can lead to inappropriate proliferation and leukemic transformation. We and others have previously described seven transcriptional regulators (heptad; LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) which bind key haematopoietic genes in normal human CD34+ haematopoietic stem and progenitor cells (HSPCs). Heptad factors form a densely interconnected circuit by binding combinatorically at their own, and each other’s, regulatory elements. However, the precise role of the heptad throughout normal and leukemic haematopoiesis, including whether all seven factors act together in single cells, and whether heptad perturbation can influence cell fate decisions remain unclear. In this study we integrate bulk and single cell data in normal human HSPCs and leukemic cells and find that chromatin conformation at key heptad regulatory elements is predictive of cell identity in normal and leukemic progenitors. The interconnected heptad circuit identified in normal HSPCs persists in AML, but single cell transcriptomics suggest that specific heptad sub-circuits exist in individual cells, and we show that GATA2, TAL1 and ERG play key roles in regulating the stem to erythroid transition in both normal and leukemic contexts.

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Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells [ChIP-seq]

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Combinatorial Transcriptional Control in Blood Stem/Progenitor Cells: Genome-wide Analysis of 10 major Transcriptional Regulators

Project description:Combinatorial transcription factor (TF) interactions control cellular phenotypes and therefore underpin stem cell formation, maintenance and differentiation. Here we report the genome-wide binding patterns and combinatorial interactions for 10 key regulators of blood stem/progenitor cells (Scl/Tal1, Lyl1, Lmo2, Gata2, Runx1, Meis1, Pu.1, Erg, Fli-1, Gfi1b) thus providing the most comprehensive TF dataset for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns followed by functional validation revealed the following: First, a previously unrecognized combinatorial interaction between a heptad of TFs (Scl, Lyl1, Lmo2, Gata2, Runx1, Erg, Fli-1). Second, we implicate direct protein-protein interactions between four key regulators (Runx1, Gata2, Scl, Erg) in stabilising complex binding to DNA. Third, Runx1+/-::Gata2+/- compound heterozygous mice are not viable with severe haematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells. 10 Samples (9 Transcription Factors and 1 Histone Modification) and 1 Control (IgG). All from the same cell line, a haematopoietic progenitor cell line (HPC-7).

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Project description:Combinatorial transcription factor (TF) interactions regulate hematopoietic stem cell formation, maintenance and differentiation, and are increasingly recognised as drivers of stem cell signatures in cancer. However, genome-wide combinatorial binding patterns for key regulators do not exist in primary human hematopoietic stem/progenitor cells (HSPCs) and have constrained analysis of the global architecture of the molecular circuits controlling these cells. Here we provide new high-resolution genome-wide binding maps of seven key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1 and LMO2) in human CD34+ HSPCs together with quantitative RNA and microRNA expression profiles. We catalogue binding of TFs at coding genes and microRNA promoters and report that combinatorial binding of all seven TFs is favoured and is associated with differential expression of genes and microRNA in HSPCs. We also uncover a hitherto unrecognized association between FLI1 and RUNX1 pairing in HSPCs, establish a correlation between the density of histone modifications, which mark active enhancers and the number of overlapping TFs at a peak and identify complex relationships between specific miRNAs and coding genes regulated by the heptad. Taken together, this study demonstrates that a heptad of TFs forms a dense auto-regulatory core in human HSPCs with binding of all seven TFs at tissue specific regulatory elements of heptad genes and collectively regulates miRNAs that in turn target components of the heptad and genes regulated by the heptad. Examination of cominatorial binding by 7 transcription factors, 1 IgG control along with mRNA and small RNA sequencing in human CD34+ cells

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