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EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE189078 | GEO | 2022/06/30

REPOSITORIES: GEO

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EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [10x]

Project description:Haematopoietic stem cells (HSC) and multipotent progenitor cells (MPP) generate all cells of the blood system, although cellular heterogeneity and bias in lineage potential have been observed. Here, we examined whether lineage-specific transcription factors, such as the B-lineage determinant EBF1, establish lineage bias in early progenitors. We detect low level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, and show that Ebf1-deficient animals display reduced HSC quiescence and repopulation capacity, enhanced myelopoiesis and enhanced myeloid differentiation potential of MPP3 and MPP4 cells. Bulk and single-cell RNA-seq analysis revealed a CEBPa-driven myeloid transcriptome in Ebf1-deficient progenitors, and we find that EBF1 binds and potentially antagonizes the haematopoietic Cebpa enhancer. In MPP3 cells, EBF1 additionally primes enhancers associated with B-lymphoid genes that gain expression in common lymphoid progenitors. Thus, our study identifies EBF1 as an important determinant in regulating the balance of myeloid versus lymphoid potential in the earliest hematopoietic progenitors.

2022-06-30 | GSE189051 | GEO

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [ATAC-seq]

2022-06-30 | GSE189049 | GEO

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [Bulk RNA-seq]

2022-06-30 | GSE188884 | GEO

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism

Project description:EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism

| PRJNA781462 | ENA

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [10x]

Project description:EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [10x]

| PRJNA781256 | ENA

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [ATAC-seq]

Project description:EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [ATAC-seq]

| PRJNA781258 | ENA

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [Bulk RNA-seq]

Project description:EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [Bulk RNA-seq]

| PRJNA780562 | ENA

C/EBPα induces Ebf1 gene expression in common lymphoid progenitors.

Project description:C/EBPα is required for formation of granulocyte-monocyte progenitors (GMP) and also participates in B lymphopoiesis. The common lymphoid progenitor (CLP) and preproB populations but not proB cells express Cebpa, and pan-hematopoietic deletion of the +37 kb Cebpa enhancer using Mx1-Cre leads not only to reduced GMP but also to 2-fold reduced marrow preproB and >15-fold reduced proB and preB cells. We now show that IL7Rα-Cre-mediated deletion of the +37 kb Cebpa enhancer, which occurs in 89% of Ly6D+ and 65% of upstream Ly6D- CLP, leads to a 2-fold reduction of both preproB and proB cells, and a 3-fold reduction in preB cells, with no impact on GMP numbers. These data support a direct role for C/EBPα during B lineage development, with reduced enhancer deletion in Ly6D- CLP mediated by IL7Rα-Cre diminishing the effect on B lymphopoiesis compared to that seen with Mx1-Cre. Amongst mRNAs encoding key transcriptional regulators that initiate B lymphoid specification (PU.1, E2A, IKAROS, EBF1, FOXO1, and BACH2), only Ebf1 levels are altered in CLP upon Mx1-Cre-mediated Cebpa enhancer deletion, with Ebf1 reduced ~40-fold in Flt3+Sca-1intc-kitintIL7Rα+ CLP. In addition, Cebpa and Ebf1 RNAs were 4- and 14-fold higher in hCD4+ versus hCD4- CLP from Cebpa-hCD4 transgenic mice. Histone modification ChIP-Seq data for CLP indicate the presence of active, intronic Ebf1 enhancers located 270 and 280 kb upstream of the transcription start sites. We identified a cis element in this region that strongly binds C/EBPα using the electrophoretic mobility shift assay. Mutation of this C/EBPα-binding site in an Ebf1 enhancer-TK-luciferase reporter leads to a 4-fold reduction in C/EBPα-mediated trans-activation. These findings support a model of B lymphopoiesis in which induction of Ebf1 by C/EBPα in a subset of CLP contributes to initiation of B lymphopoiesis.

| S-EPMC7746190 | biostudies-literature

Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches.

Project description:Although haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche, most published experimental manipulations of the HSC niche have affected the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs and restricted progenitors reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine CXCL12 for HSC and restricted progenitor maintenance. Cxcl12(DsRed) knock-in mice (DsRed-Express2 recombined into the Cxcl12 locus) showed that Cxcl12 was primarily expressed by perivascular stromal cells and, at lower levels, by endothelial cells, osteoblasts and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or nestin-cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12 from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12 from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cells into circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors but not HSCs or myeloerythroid progenitors, and did not mobilize these cells into circulation. Different stem and progenitor cells thus reside in distinct cellular niches in bone marrow: HSCs occupy a perivascular niche and early lymphoid progenitors occupy an endosteal niche.

| S-EPMC3600153 | biostudies-literature

Myelo-lymphoid lineage restriction occurs in the human haematopoietic stem cell compartment before lymphoid-primed multipotent progenitors.

Project description:Capturing where and how multipotency is lost is crucial to understand how blood formation is controlled. Blood lineage specification is currently thought to occur downstream of multipotent haematopoietic stem cells (HSC). Here we show that, in human, the first lineage restriction events occur within the CD19-CD34+CD38-CD45RA-CD49f+CD90+ (49f+) HSC compartment to generate myelo-lymphoid committed cells with no erythroid differentiation capacity. At single-cell resolution, we observe a continuous but polarised organisation of the 49f+ compartment, where transcriptional programmes and lineage potential progressively change along a gradient of opposing cell surface expression of CLEC9A and CD34. CLEC9AhiCD34lo cells contain long-term repopulating multipotent HSCs with slow quiescence exit kinetics, whereas CLEC9AloCD34hi cells are restricted to myelo-lymphoid differentiation and display infrequent but durable repopulation capacity. We thus propose that human HSCs gradually transition to a discrete lymphoid-primed state, distinct from lymphoid-primed multipotent progenitors, representing the earliest entry point into lymphoid commitment.

| S-EPMC6173731 | biostudies-literature

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