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Glycosylation Orchestrates Megakaryocytic Fate of Hematopoietic Stem Cells via Wnt-Muc13 Signaling [bulkRNA]

ABSTRACT: The cell-intrinsic and extrinsic programs governing hematopoietic stem and progenitor cells (HSPCs) cell fate determination remain unresolved. Our data reveals that loss of B4GALT1 glycosyltransferase biosynthetic activity restricts HSPC N- and O-glycosylation and reprograms previously unrecognized N-glycan gradients in the bone marrow environment with high expression of complex N-glycans in HSPC-rich regions to accumulate aberrant, cancer-like N-glycan signatures. The loss of B4GALT1 increases the expression of aberrantly glycosylated intracellular oncogenic Mucin13, which is likely to disrupt the destruction complex and mediate Wnt/β-catenin hyperactivation. This enhances metabolic and cell cycle activity, expands the megakaryocyte-primed stem cell pool, and promotes emergence from a steady state, highlighting the essential role of B4GALT1 in modulating the BM glycosylation landscape and its significance in regulating the expansion and differentiation of HSPCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE263934 | GEO | 2026/06/03

REPOSITORIES: GEO

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Glycosylation Orchestrates Megakaryocytic Fate of Hematopoietic Stem Cells via Wnt-Muc13 Signaling [scRNA]

Project description:The cell-intrinsic and extrinsic programs governing hematopoietic stem and progenitor cells (HSPCs) cell fate determination remain unresolved. Our data reveals that loss of B4GALT1 glycosyltransferase biosynthetic activity restricts HSPC N- and O-glycosylation and reprograms previously unrecognized N-glycan gradients in the bone marrow environment with high expression of complex N-glycans in HSPC-rich regions to accumulate aberrant, cancer-like N-glycan signatures. The loss of B4GALT1 increases the expression of aberrantly glycosylated intracellular oncogenic Mucin13, which is likely to disrupt the destruction complex and mediate Wnt/β-catenin hyperactivation. This enhances metabolic and cell cycle activity, expands the megakaryocyte-primed stem cell pool, and promotes emergence from a steady state, highlighting the essential role of B4GALT1 in modulating the BM glycosylation landscape and its significance in regulating the expansion and differentiation of HSPCs.

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Glycosylation Orchestrates Megakaryocytic Fate of Hematopoietic Stem Cells via Wnt-Muc13 Signaling [scMultiome]

Project description:Hematopoietic stem and progenitor cells (HSPCs) sustain blood production through tightly regulated fate decisions. Disruption of this control underlies disorders such as myelodysplastic syndromes, myeloproliferative neoplasms, and inherited thrombocytopenias. While transcriptional and epigenetic regulation of HSPCs is well established, the contribution of glycosylation has remained largely unexplored. Here, we identify the glycosyltransferase B4GALT1 as a central regulator of hematopoiesis that integrates extrinsic niche cues with intrinsic transcriptional programs. B4GALT1 shapes the bone marrow microenvironment by generating complex glycan niches that support HSPC function. However, its deficiency produces oncogenic glycan signatures, disrupts HSPC niche integrity, and induces aberrant expression of Mucin 13 (MUC13). These changes expand stem and progenitor pools, enforce megakaryocyte lineage bias, and activate the Wnt–MUC13/β-catenin signaling axis, a pathway tightly linked to proliferation and malignant transformation. Consequently, B4GALT1 loss uncouples proliferation from self-renewal, altering key regulators of stem cell quiescence, lineage balance, and marrow homeostasis. Our findings define a previously unrecognized glycan-dependent regulatory axis that directs HSPC fate through coordinated transcriptional reprogramming, signaling modulation, and niche remodeling. This work establishes aberrant glycosylation as a driver of hematopoietic dysfunction and highlights B4GALT1 as a potential therapeutic target in stem cell–driven blood disorders.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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