Dataset Information

Effect of Copper deficiency on gene expression of Lin-c-Kit cell in the bone marrow of mice

ABSTRACT: Copper homeostasis has been linked to human health and hematopoiesis. However, the underlying mechanisms remain elusive. Here, we demonstrate the pivotal role of the transporter Slc31a1(Ctr1) in copper uptake, during postnatal hematopoiesis. Specifically, Slc31a1-mediated copper transport sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells (HSCs). By transcriptome analyses we reveal a disrupted differentiation program in the hematopoietic stem and progenitor cells (HSPCs) derived from diet-induced copper deficiency mice or hematopoietic-specific Slc31a1 knockout (vKO) mice. Further, we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via Complex IV within HSPCs. Notably, the copper ionophore elesclomol significantly ameliorates severe anemia in vKO mice and partially recovers mitochondrial function in vKO HSPCs. These findings demonstrate the critical role of Slc31a1/copper in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism; thus, shedding light on the molecular basis of HSC fate decisions while opening new avenues to maintaining functional HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE275760 | GEO | 2025/12/31

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Hematopoietic stem cells (HSCs) with certain somatic mutations, most commonly in the DNA methyltransferase DNMT3A, gain a clonal growth advantage leading to the development of clonal hematopoiesis (CH). The distinct functional differences that allow DNMT3A-mutant HSCs to gain a fitness advantage and outcompete wild-type HSC in the context of aging are not fully elucidated. We recently discovered that HSC aging is initiated by decline in local production of insulin-like growth factor 1 (IGF1). Here, we used a mouse model of DNMT3A-mutant CH (Dnmt3aR878H/+) to investigate the extent to which decline in IGF1 alters the selective advantage of Dnmt3aR878H/+ HSCs. Upon transplant into IGF1-deficient recipient mice, Dnmt3aR878H/+ HSCs gained enhanced selective advantage over wild-type HSCs and maintained lineage balanced blood production. As IGF1/mTOR signaling is well understood to regulate energy metabolism, we investigated underlying metabolic differences between Dnmt3aR878H/+ and wild-type HSCs. Dnmt3aR878H/+ HSPCs had similar glycolytic capacity as wild-type HSCs but enhanced mitochondrial reserve capacity and mitochondrial activation potential. To evaluate whether mitochondrial function is a targetable dependency of Dnmt3aR878H/+ HSCs, we administered the mitochondrial-targeted molecule MitoQ resulting in the depletion of their mitochondrial reserve capacity. We find that MitoQ reduces the competitive advantage of Dnmt3aR878H/+ hematopoiesis. To identify the mechanism(s) by which MitoQ alters Dnmt3aR878H/+ phenotypic expansion we evaluated transcriptional changes after MitoQ treatment and find altered response to Igf1/mTOR signaling compared to wild-type HSC. The altered response to Igf1/mTOR signaling in part mediates the Dnmt3aR878H/+ hematopoietic selective advantage. Taken together, our work supports that mitochondrial metabolic regulation is a key mechanism by which DNMT3A-mutant HSCs gain a selective advantage. Targeting this mechanism may maintain polyclonal hematopoiesis during aging and reduce the risk of CH-associated disease.

Dataset Information

Effect of Copper deficiency on gene expression of Lin-c-Kit cell in the bone marrow of mice

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets