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Deep learning identifies Pbx1 as a network hub of hematopoietic stem cell aging [Pbx1 RNA-seq]

ABSTRACT: Hematopoietic stem cells (HSCs) constitute a well-structured hematopoietic system that undergoes an age-related bias toward myeloid/platelet differentiation. The mechanism by which this aging hallmark is deeply embedded in intrinsic HSC programs is unknown. Using single-cell RNA-seq data, old HSCs harbor two distinct transcriptional programs: one shared with megakaryocytes and the other associated with the most primitive HSCs. By employing a transformer-based model that captures higher-order differences between young and aging HSCs and integrating time-series transcriptomic analyses, epigenetic studies, and comprehensive transcription factor screens, we identified Pbx1 as a central gene controlling both age-related transcriptional programs and differentiation defects in old HSCs. Pbx1 suppresses erythroid differentiation by repressing Gata1 expression. In addition, we found that the histone methyltransferase G9a/GLP acts as an epigenetic regulator that specifically inhibits Gata1 expression and erythroid differentiation. These findings provide insight into the differentiation defects associated with stem cell aging and potential strategies for rejuvenation.

ORGANISM(S): Mus musculus

PROVIDER: GSE286961 | GEO | 2026/07/13

REPOSITORIES: GEO

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Deep learning identifies Pbx1 as a network hub of hematopoietic stem cell aging [Pbx1 Cut&Tag]

Project description:Hematopoietic stem cells (HSCs) constitute a well-structured hematopoietic system that undergoes an age-related bias toward myeloid/platelet differentiation. The mechanism by which this aging hallmark is deeply embedded in intrinsic HSC programs is unknown. Using single-cell RNA-seq data, old HSCs harbor two distinct transcriptional programs: one shared with megakaryocytes and the other associated with the most primitive HSCs. By employing a transformer-based model that captures higher-order differences between young and aging HSCs and integrating time-series transcriptomic analyses, epigenetic studies, and comprehensive transcription factor screens, we identified Pbx1 as a central gene controlling both age-related transcriptional programs and differentiation defects in old HSCs. Pbx1 suppresses erythroid differentiation by repressing Gata1 expression. In addition, we found that the histone methyltransferase G9a/GLP acts as an epigenetic regulator that specifically inhibits Gata1 expression and erythroid differentiation. These findings provide insight into the differentiation defects associated with stem cell aging and potential strategies for rejuvenation.

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The H3K4 methyltransferase KMT2D is an essential cofactor for GATA1 at erythroid gene enhancers

Project description:Gene expression during cellular differentiation is coordinated by combinatorial interactions between transcription factors (TFs) and cofactors at promoters and enhancers. The “master TF” GATA1 coordinates gene transcription in a subset of hematopoietic lineages, including erythroid, megakaryocytic, mast, and eosinophil, while repressing the development of other blood lineages. However, the specific cofactors required for GATA1-activated gene expression during hematopoiesis are incompletely defined. We identified the cofactor KMT2D, an H3K4 methyltransferase that collaborates with H3K27 acetyltransferases to activate transcription, in an unbiased CRISPR/Cas9 screen for epigenetic regulators of erythropoiesis. Loss of KMT2D in human erythroid precursors caused developmental arrest with impaired expression of numerous erythroid genes. Mechanistically, KMT2D colocalized with GATA1 on more than one thousand erythroid enhancers associated with over two hundred erythroid genes. In general, co-occupancy of GATA1 and KMT2D at erythroid enhancers was associated with stronger transcriptional activity than occupancy by GATA1 alone. Acute depletion of KMT2D in erythroid precursors caused rapid reductions of H3K4me1 and H3K27ac on a subset of GATA1-bound enhancers and impaired the expression of canonical erythroid genes, including ZFPM1, SLC4A1, and EPOR. Moreover, acute depletion of GATA1 or KMT2D individually caused downregulation of overlapping gene sets. Thus, KMT2D controls erythropoiesis by selectively activating GATA1-dependent erythroid enhancers. Our studies identify KMT2D as a novel cofactor for transcriptional activation by GATA1 during erythropoiesis. More generally, our findings demonstrate how a lineage-specific TF cooperates with a ubiquitous epigenetic regulator to drive lineage-specific gene expression during cellular differentiation.

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Differentially regulated genes in LT-HSC from control or Pbx1-null mice

Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes are associated with the Tgf-b pathway, which serves a major role in maintaining HSC quiescence. Pbx1-deficient LT-HSCs are unable to up-regulate the cyclin dependent kinase inhibitor p57 in response to Tgf-b, providing a mechanism through which Pbx1 maintenance of stem cell self-renewal is achieved. Keywords: genetic modification

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Project description:Developmental transcription factors act in networks, but how these networks achieve cell- and tissue specificity is still poorly understood. We here explored pre-B-cell leukemia homeobox 1 (PBX1) in adult neurogenesis combining genomic, transcriptomic, and proteomic approaches. ChIP-Seq analysis uncovered PBX1 binding to a wide range of different genes. Integration of PBX1 ChIP-seq with ATAC-seq data predicted interaction partners, which were subsequently validated by mass-spectrometry. Spatial transcriptomics revealed distinct temporal expression dynamics of Pbx1 and interacting factors. Among these were class I bHLH proteins TCF3, TCF4 and TCF12. RNA-seq upon Pbx1, Tcf3 and Tcf4 knockdown identified proliferation and differentiation associated genes as shared targets. Neuronal differentiation was reduced upon depletion of either factor, suggesting functional cooperation between PBX1 and TCF3/4. Notably, while physiological PBX1-TCF interactions have not yet been described, chromosomal translocation resulting in genomic TCF3::PBX1 fusion characterizes a subtype of acute lymphoblastic leukemia. Introducing Pbx1 into Nalm6 cells, a pre B-cell line expressing TCF3 but lacking PBX1, upregulated leukemogenic genes including BLK and NOTCH3, arguing that functional PBX1-TCF cooperation likely extends to hematopoietic contexts. Our study hence uncovers a PBX1-TCF module orchestrating the balance between progenitor cell proliferation and differentiation in adult neurogenesis with implications for leukemia etiology.

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