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GFI1 regulates NK cell maturation and function [scMultiome-seq].

ABSTRACT: Natural killer cells defend against malignancies and viral infections through a tightly controlled program of differentiation and maturation. However, the transcriptional mechanisms guiding this process remains incompletely defined. Using paired single cell multiomic profiling, we show that the transcriptional repressor GFI1 epigenetically regulates key molecular programs, including EOMES and T-BET balance, to promote NK cell proliferation and transition from immature to terminally differentiated NK stages. GFI1 was shown to repress FOXO1 chromatin accessibility in mature NK cells, which normally represses NK cell proliferation and maturation. Co-deletion of both GFI1 and FOXO1 largely rescued NK cell differentiation identifying a critical GFI1-FOXO1 axis essential for protection against tumour metastasis. These findings position GFI1 as an important transcriptional node integrating NK cell differentiation, activation, and effector programming.

ORGANISM(S): Mus musculus

PROVIDER: GSE313719 | GEO | 2026/03/13

REPOSITORIES: GEO

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Project description:GFI1 is a transcriptional repressor protein that plays an essential role in HSCs development, lymphoid and myeloid differentiation and Acute Myeloid Leukaemic (AML) pathogenesis. Low expression levels of GFI1 is associated with a poor prognosis in AML development. In addition, a single nucleotide polymorphism (SNP) variant of GFI1 results in the generation of GFI1 protein with asparagine (N) instead of serine (S) at the 36th amino acid position, known as GFI136N. Expression of the GFI1-36N allele leads as well to poor prognosis and promotes AML development. In this study, we demonstrated with the help of RNAseq transcriptomic analysis that the presence of GFI1-36N is associated with increased frequency of chromosomal aberrations and mutational burden in murine and human AML cells. In particular, GFI1-36N modulates DNA repair pathways, O6-methylguanine-DNA-methyltransferase (MGMT)-mediated repair and homologous recombination repair (HR). Mechanistically, GFI1-36N exhibits impaired binding to Ndrg1 promoter element compared to GFI1-36S (wild type), causing decreased NDRG1 levels, consequently leading to suppression of MGMT expression, imprinted at the transcriptome and proteome, thus leaving the AML cells vulnerable to DNA damaging agents. Furthermore, we showed that a low expression level of GFI1 in leukemic cells is associated with high OXPHOS and enhanced glutamine metabolism. However, we hypothesise that the observed metabolic phenotype is mediated through FOXO1 protein. RNAseq transcriptomic analysis revealed higher Foxo1 mRNA expression levels with lower GFI1 expression, providing the first hint of Foxo1 as a potential target gene of GFI1 protein. The mRNA and protein levels of high Foxo1 with reduced GFI1 expression was confirmed by RT-PCR and western blot, respectively. In addition, CHIPseq and ATACseq analysis further proved that Foxo1 is a potential target gene of GFI1. In summary, we show that GFI1 plays a role during DNA repair and metabolism and thus provides critical insights into a novel therapeutic option for AML patients carrying the GFI1-36N variant or having a low expression level of GFI1.

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GFI1 regulates NK cell maturation and function [scMultiome-seq].

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