Chromatin accessibility profiling of wild-type and Slc31a1 conditional knockout mouse bone marrow stromal cells by ATAC-seq
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE337266 | GEO | 2026/07/31
REPOSITORIES: GEO
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Project description:Age-associated bone loss is largely driven by impaired osteoblast generation from bone marrow stromal cells (BMSCs), but the metabolic and epigenetic mechanisms that regulate osteogenic commitment remain incompletely understood. This study identifies SLC31A1-mediated copper uptake as a cell-intrinsic metabolic checkpoint required for BMSC osteogenic differentiation and skeletal integrity. Mesenchymal lineage-specific Slc31a1 deletion impaired bone formation and BMSC osteogenesis and caused Slc31a1-deficient BMSCs to accumulate in an ID1-high progenitor-like state. To investigate the epigenetic mechanism underlying this phenotype, H3K9ac ChIP-seq was performed in wild-type and Slc31a1 conditional knockout mouse BMSCs. The analysis revealed increased H3K9ac enrichment in Slc31a1-deficient BMSCs, including enhanced H3K9ac signal at the Id1 locus, supporting a model in which SLC31A1-dependent copper uptake maintains mitochondrial complex IV integrity and NAD+ homeostasis to enable SIRT1-dependent epigenetic repression of Id1 during osteogenic commitment.
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Project description:Age-associated bone loss is largely driven by impaired osteoblast generation from bone marrow stromal cells (BMSCs), but the metabolic constraints that limit osteogenic commitment remain incompletely defined. In this study, we identify SLC31A1-mediated copper uptake as a cell-intrinsic metabolic checkpoint for BMSC osteogenic differentiation and skeletal integrity. This single-cell RNA-seq dataset profiles adherent bone marrow stromal cells isolated from wild-type Slc31a1flox/flox mice and mesenchymal lineage-specific Slc31a1 conditional knockout mice (Prrx1-Cre+/-; Slc31a1flox/flox). Single-cell transcriptomic analysis resolved Prrx1-positive osteogenic-lineage populations, including BMSC subsets and pre-osteoblasts, and revealed that Slc31a1-deficient BMSCs accumulate in an ID1-high progenitor state and fail to efficiently transition toward osteogenic commitment. Together with functional, metabolic, and epigenomic analyses, these data support a copper-mitochondria-NAD-SIRT1-ID1 axis that links trace metal uptake to stem/progenitor cell fate decisions and identifies intracellular copper availability as a reversible metabolic vulnerability in skeletal aging.
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