Computational insights into the regulatory role and functional significance of NOTCH1 intronic SNP rs3124599 and its link to NPC.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a multifactorial disease driven by both genetic and environmental factors. The neurogenic locus notch homolog 1 (NOTCH1) gene has dual oncogenic and tumor-suppressive effects that depend on the cellular context. An intronic single nucleotide polymorphism (SNP) in NOTCH1, rs3124599, has been linked to various diseases. However, its involvement in NPC remains unknown. This study aims to explore the regulatory and susceptibility effects of rs3124599 on NPC. METHODS: Integrative computational analyses were performed using various bioinformatics tools and databases. These included RegSNPs-intron, PredictSNP, RegulomeDB, HaploReg v4.2, SNP2TFBS, atSNP, SNPnexus, eQTLGen, and GTEx. We used these resources to assess potential effects of rs3124599 on splicing, TF binding, chromatin accessibility, histone modifications, and gene expression. RESULTS: The intronic SNP rs3124599 is located in an epigenetically dynamic region. This region is enriched with active histone marks and DNase I hypersensitivity (DHS) sites. These features consistent with open chromatin. Motif analyses revealed disrupted binding affinities for significant TFs, including EGR2-4, PLAG1, NFE2, MYC, and FOXO3, indicating regulatory disruption. FunSeq2 predicted this SNP to be deleterious (score = 0.90). eQTL analysis validated its cis-regulatory function, revealing that it activated DNLZ, INPP5E, and SEC16A and repressed GPSM1 and CARD9. No significant findings were observed for lncRNA and miRNA. CONCLUSION: Despite its intronic location, SNP rs3124599 lies within an epigenetically regulated region that modifies NOTCH1 expression and NPC susceptibility at the chromatin/transcriptional level. Experimental validation is highly recommended to elucidate its role in NOTCH1 regulation and NPC progression.