Functional Genome Analysis for Immune Cells Provides Clues for Stratification of Systemic Lupus Erythematosus

Fujio, Keishi

doi:10.3390/biom13040591

Cited by 5 publications

(4 citation statements)

References 49 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite its reliance on a limited sample size, the study reports significantly elevated SLC15A4 mRNA in PBMCs from SLE patients compared to healthy controls. This observation bolsters the association between SLC15A4 expression and autoimmune diseases such as SLE (50).…”

Section: Discussionsupporting

confidence: 58%

“…Immune dysregulation, wherein an overactive immune system generates autoantibodies against the body's cells and tissues, is a hallmark of SLE. Furthermore, the fact that SLE is characterized by heightened levels of type I interferons (IFN-I) makes the association between SLC15A4 and IFN-I production especially noteworthy (17,50,52). Excessive IFN-I production is a significant contributor to SLE pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A non-coding variant in SLC15A4 modulates enhancer activity and lysosomal deacidification linked to lupus susceptibility

Singh,

Maiti,

Rallabandi

et al. 2023

Front. Lupus

View full text Add to dashboard Cite

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the SLC15A4 gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown.MethodsTo address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of SLC15A4.ResultsThrough luciferase reporter assays followed by chromatin immunoprecipitation (ChIP)-qPCR, we observed significant allele-specific enhancer effects of rs35907548 in diverse cell lines. The rs35907548 risk allele T is associated with increased regulatory activity and target gene expression, as shown by eQTLs and chromosome conformation capture (3C)-qPCR. The latter revealed long-range chromatin interactions between the rs35907548 enhancer and the promoters of SLC15A4, GLTLD1, and an uncharacterized lncRNA. The enhancer-promoter interactions and expression effects were validated by CRISPR/Cas9 knock-out (KO) of the locus in HL60 promyeloblast cells. KO cells also displayed dramatically dysregulated endolysosomal pH regulation.ConclusionsTogether, our data show that the rs35907548 risk allele affects multiple aspects of cellular physiology and may directly contribute to SLE.

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

A non-coding variant in SLC15A4 modulates enhancer activity and lysosomal deacidification linked to lupus susceptibility

Singh,

Maiti,

Rallabandi

et al. 2023

Front. Lupus

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 58%

A Non-Coding Variant inSLC15A4Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility

Maiti

Singh

Reddy-Rallabandi

et al. 2023

Preprint

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the SLC15A4 gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown. To address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of SLC15A4. Through luciferase reporter assays followed by chromatin immunoprecipitation-qPCR, we identified significant allele-specific enhancer effects of rs35907548 in diverse cell lines. The rs35907548 risk allele T is associated with increased regulatory activity and target gene expression, as shown by eQTLs and chromosome conformation capture (3C)-qPCR. The latter revealed long-range chromatin interactions between the rs35907548 enhancer and the promoters of SLC15A4, GLTLD1, and an uncharacterized lncRNA. The enhancer-promoter interactions and expression effects were validated by CRISPR/Cas9 knock-out of the locus in HL60 promyeloblast cells. Further, KO cells had dysregulated endolysosomal pH. This study highlights the significance of a non-coding variant, rs35907548, which may have a direct impact on the underlying regulatory mechanisms associated with SLE.

show abstract

“…unpublished data). Actually, the analysis using the expression quantitative trait loci (eQTL) database, ImmuNexUT, has shown that the expression of SLC15A4 is increased in individuals with SLE-risk genotypes ( 45 ). A further analysis of the functional significance of SNPs in pathogenesis is needed, as with other disease-related SNPs; however, the above observation obtained by an eQTL analysis is consistent with the results of animal model experiments, indicating that SLC15A4 plays a role in lupus pathogenesis.…”

Section: Control Of Mtorc1 By Slc15a4mentioning

confidence: 99%

Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities

Kobayashi,

Toyama-Sorimachi

2023

Front. Immunol.

View full text Add to dashboard Cite

Amino acid transporters are generally recognized as machinery that transport amino acids from the extracellular environment into the cytoplasm. Although their primary function is the uptake of amino acids to supply the cell with nutrients and energy, endolysosome-resident amino acid (EL-aa) transporters possess several unique functions in accordance with their localization in intracellular vesicular membranes. They play pivotal roles in the maintenance of metabolic homeostasis via direct involvement in the amino acid sensing pathway, which regulates the activity of mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular metabolism. Additionally, some EL-aa transporters contribute to the maintenance of dynamic homeostasis of endolysosomes, including the regulation of endolysosomal acidity, by carrying amino acids out of endolysosomes. In addition, EL-aa transporters act as a scaffold to gather signaling molecules and multiple enzymes to control cellular metabolism on the endolysosomal membrane. Among EL-aa transporters, solute carrier family 15 member 4 (SLC15A4) is preferentially expressed in immune cells, including macrophages, dendritic cells, and B cells, and plays a key role in the integration of metabolic and inflammatory signals. In this review, we summarize our recent findings on EL-aa transporter contributions to inflammatory and metabolic signaling in the endolysosomes of immune cells by focusing on the SLC15 family, including SLC15A4 and SLC15A3, and discuss their uniqueness and universality. We also discuss the potential of targeting these EL-aa transporters in immune cells for the development of novel therapeutic strategies for inflammatory diseases. Because these transporters are highly expressed in immune cells and significantly alter the functions of immune cells, targeting them would provide a great advantage in ensuring a wide safety margin.

show abstract

Functional Genome Analysis for Immune Cells Provides Clues for Stratification of Systemic Lupus Erythematosus

Cited by 5 publications

References 49 publications

A non-coding variant in SLC15A4 modulates enhancer activity and lysosomal deacidification linked to lupus susceptibility

A non-coding variant in SLC15A4 modulates enhancer activity and lysosomal deacidification linked to lupus susceptibility

A Non-Coding Variant inSLC15A4Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility

Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities

Contact Info

Product

Resources

About