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CMaf supports Zeb2 expression for primitive hematopoiesis (CUT&RUN)

ABSTRACT: Microglia arise exclusively from yolk sac (YS) progenitors during primitive hematopoiesis, while other tissue resident macrophages (TRMs)originate during transient-definitive and definitive hematopoiesis. Macrophages require the transcriptional repressor Zeb2 for development, and macrophages developing during definitive hematopoiesis require the ‒165 kb Zeb2 enhancer. However, microglia develop normally in Zeb2 ‒165kb mice lacking this enhancer, indicating that a distinct genetic program supports macrophage development in primitive hematopoiesis. Here, we identify the molecular basis that distinguishes macrophage development in primitive vs. definitive hematopoiesis. We show that all tissue resident macrophages (TRMs) that develop in Zeb2 ‒165kb mice arise exclusively during primitive hematopoiesis, showing that even erythro-myeloid progenitors (EMPs) from the transient-definitive stage rely on the ‒165 Zeb2 enhancer. Next, we identified the transcription factors Maf and Jun as being expressed by yolk sac (YS) progenitors during primitive hematopoiesis, but not by progenitors during definitive hematopoiesis. Further, we find that Maf and Jun together induce Zeb2 expression independently of the ‒165 kb Zeb2 enhancer and restore macrophage development from adult bone marrow progenitors in Zeb2 ‒165kb mice. Finally, Maf-deficient embryos show severe ablation of microglia development, confirming the in vivo requirement for Maf in supporting Zeb2 during primitive hematopoiesis. These results illustrate distinct transcriptional pathways controlling macrophage development during primitive and subsequent waves of hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE304528 | GEO | 2025/12/26

REPOSITORIES: GEO

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cMaf supports Zeb2 expression for primitive hematopoiesis (Multiome)

Project description:Tissue-resident macrophages (TRMs) are essential for tissue homeostasis and play a key role in disease and pathology. They originate from distinct waves of hematopoietic progenitors, including primitive, transient-definitive, and definitive hematopoiesis. We found that loss of the Zeb2 ‒165kb enhancer impairs monocyte development and alters TRM transcriptional landscapes, with only HSC-derived monocytes requiring Zeb2 for their development. In Zeb2∆‒165kb mice, primitive TRMs persist in tissues due to the lack of replacement by later hematopoietic waves, and Maf is required for maintaining Zeb2 expression in primitive macrophages.

2025-12-26 | GSE283596 | GEO

cMaf supports Zeb2 expression for primitive hematopoiesis (FL mono RNA-seq)

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cMaf supports Zeb2 expression for primitive hematopoiesis (TRM RNA-seq)

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Hi-C2 of mouse splenic macrophages and pDCs

Project description:The transcriptional repressor Zeb2 regulates development of many cell fates among somatic, neural and hematopoietic lineages, but the basis for its requirement in these diverse linages is unclear. Our recent study uncovered a mutually repressive regulatory circuit between Id2 and Zeb2, and predicted that Zeb2 should be positively regulated by members of the E protein family of transcription factors. Here, we identified a 400bp enhancer region located 165 kilobases (kb) upstream of the Zeb2 transcriptional start site (TSS) that binds the E proteins E2A and E2-2 at several E-box motifs and is active in hematopoietic lineages. Germline deletion of this 400bp region (Zeb2 –165–/– mice) specifically prevented Zeb2 expression in hematopoietic stem cell (HSC) derived lineages. Zeb2 –165–/– mice lacked development of pDCs, monocytes, and B cells. Surprisingly, all macrophages in Zeb2 –165–/– mice were exclusively of embryonic origin. Using single-cell chromatin profiling, we identified a second Zeb2 enhancer located at +164kb that is selectively active in embryonically derived lineages, but not in lineages derived from HSCs. Thus, Zeb2 expression in adult, but not embryonic, hematopoiesis is selectively controlled by the –165kb Zeb2 enhancer.

2021-11-10 | GSE171564 | GEO

MYB is an essential regulator of primitive human hematopoiesis in human pluripotent stem cell differentiation cultures.

Project description:MYB is well recognized to be a key regulator of definitive hematopoiesis that plays an important role in the maintenance and multilineage differentiation of hematopoietic stem cells (HSCs). In the vertebrate developmental context, MYB is widely regarded dispensable for primitive hematopoiesis but critically required for the development of definitive hematopoiesis. To explore the role of MYB in human hematopoietic development we have inactivated the gene by bi-allelic TALEN-supported gene targeting in several lines of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), and subjected these cells to hematopoietic differentiation in well-defined cell culture conditions. Venus gene reporter was inserted into the knock-in allele to monitor MYB expression during the course of the hESC/iPSC differentiation. The gene reporter system showed that MYB is specifically expressed during hematopoietic commitment in the earliest primitive blood cells. Moreover, the level of MYB expression was highest at the commitment stage of differentiation and significantly decreased at the maturations stage. We found that MYB was not required for initial hematopoietic commitment of nascent mesoderm and emergence of primitive, yolk sac-type human hematopoietic progenitors. However, inactivation of MYB severely abrogated proliferation of the primitive erythroid and mixed erythroid-macrophage-megakaryocyte progenitors. In addition, MYB-negative hESC/iPSC lines demonstrated major defects in myeloid cell development and completely failed to generate mature granulocytes. Transposon-mediated rescue of MYB expression in MYB-null cells efficiently restored both the primitive hematopoietic progenitors and immature myeloid cells. Our data indicate that in contrast to its previously attributed exclusive role in definitive hematopoiesis, MYB is indispensable for primitive human hematopoiesis.

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Transcription profiling of mouse runx1-/- (AML) mutant primitive erythroid

Project description:Targeted disruption of the Runx1/ AML1 gene in mice has demonstrated that it is required for the emergence of definitive hematopoietic cells, but that it is not essential for the formation of primitive erythrocytes. These findings led to the conclusion that Runx1 is a stage-specific transcription factor acting only during definitive hematopoiesis. However, the zebrafish and Xenopus homologues of Runx1 have been shown to play roles in primitive hematopoiesis, suggesting that mouse Runx1 might also be involved in the development of primitive lineages. In order to identify differentially expressed genes in runx1-/- primitive erythroid, we carried out microarray analysis. Experiment Overall Design: Total RNA from E10.5 wild type and Runx1â??/â?? yolk sacs was extracted, and gene expression patterns were compared.

2008-06-11 | E-GEOD-10348 | biostudies-arrayexpress

Identification of differentially expressed genes in runx1-/- primitive erythroid

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Project description:Definitive hematopoiesis generates hematopoietic stem/progenitor cells (HSPCs) that give rise to all mature blood and immune cells, but remains poorly defined in human. Here, we resolve human hematopoietic populations at the earliest hematopoiesis stage by single-cell RNA-seq. We characterize the distinct molecular profiling between early primitive and definitive hematopoiesis in both human embryonic stem cell (hESC) differentiation and early embryonic development. We generate definitive HSPCs from hESCs that hold the multipotency to differentiate various blood and immune cells, as validated by single-cell clonal assay. Strikingly, the generated HSPCs from hESCs give rise to various blood and lymphoid lineages in vivo. Lastly, we characterize gene-expression dynamics in definitive and primitive hematopoiesis and reveal an unreported role of ROCK-inhibition in enhancing human definitive hematopoiesis. Our study provides a prospect for understanding human early hematopoiesis and a firm basis to generate blood and immune cells for clinical purposes.

2020-12-09 | GSE148215 | GEO

Chd1 is essential in the endothelial lineage for the emergence of definitive hematopoietic stem/progenitor cells

Project description:Lineage specification during development involves reprogramming of chromatin states, but little is known about how this is regulated in vivo. We previously showed that the chromatin remodeler Chd1 regulates transcriptional output and self-renewal of mouse embryonic stem cells, and is essential for epiblast development. These results raise the question of whether Chd1 regulates the development of other progenitor populations. Here we report that endothelial-specific deletion of Chd1 using Tie2-Cre leads to embryonic lethality by E15.5. Development of the vasculature and of primitive hematopoiesis appears to occur normally in the mutants. However, mutant embryos show signs of anemia as early as E11.5, are depleted of definitive hematopoietic stem /progenitor cells, and display a complete failure of fetal liver erythropoiesis. While mutants at E10.5 appear morphologically normal and can develop hemogenic clusters in the dorsal aorta, the E10.5 mutant endothelium fails to activate a transcriptional program associated with hematopoiesis. This transcriptional program may serve as a resource for the identification of novel markers or regulators of definitive hematopoiesis. Finally, hematopoietic-specific Chd1 deletion using Vav-Cre yields no apparent defects during development or adulthood. These results suggest that Chd1 regulates chromatin-remodeling events critical for a specific developmental window during the transition of endothelial cells to definitive blood progenitors. Analysis of CD31+ tdTomato+ cells sorted from E10.5 whole embryos with an endothelial-specific deletion of Chd1, using 4 biological replicates of 2 genotypes (CreHet controls vs mutants).

2015-03-01 | E-GEOD-62796 | biostudies-arrayexpress

Ablation of cDC2 specification by triple mutations in the Zeb2 enhancer [ChIP-Seq]

Project description:The divergence of the common dendritic cell progenitor (CDP) into specified progenitors for the cDC1 and cDC2 dendritic cells subsets is poorly understood. Some transcription factors (TFs) act in commitment of already specified progenitors, such as Batf3 which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer, but the mechanism of CDP divergence remains unknown. Here, we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis suggested that Nfil3 acts upstream of Id2, Batf3, and Zeb2 in cDC1 development but has not revealed its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and ChIP-seq analysis identified endogenous NFIL3 binding in the –165 kb Zeb2 enhancer at three sites that also bind CCAAT-enhancer-binding proteins C/EBPa and C/EBPb. In vivo mutational analysis using CRISPR/Cas9 targeting showed that these NFIL3/C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites, respectively. Mutation of all three NFIL3/C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice failed to generate TH2 responses against H. polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths. Thus, CDP divergence is controlled by competition between NFIL3 and C/EBPs at the –165 kb Zeb2 enhancer.

2022-04-19 | GSE174108 | GEO

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