Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.10.27.684937

Identification and functional characterization of an AMD associated c-ABL binding SNP streak within the ARMS2 gene promoter region

Zhang, P.-W.·Liu, S.·Li, W.·Fan, L.·Li, S.·Wan, Z.-H.·Berlinicke, C. A.·Merbs, S. L.·Zack, D. J.
View original source ↗Export metadata ↓

Abstract

BackgroundLarge-scale genome-wide association studies (GWAS) have identified the human 10q26 locus as a major genetic risk factor for age-related macular degeneration (AMD). The AMD-associated interval has been refined to a 5,196 bp segment flanking the ARMS2-HTRA1 region, excluding HTRA1 and the ARMS2 3' indel (443del54ins) variant by risk haplotype analysis. Although the missense SNP rs10490924 has been proposed as a functional variant, its role in AMD remains controversial, and the causative variants and underlying mechanisms within this region remain unresolved. MethodsAn unbiased bioinformatic screen identified a 5-SNP block within the 5,196 bp interval that potentially alters c-ABL protein binding. Protein-DNA interactions were validated using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Genetic association with AMD (dry and wet subtypes) was assessed in patient cohorts using blood genomic DNA. The regulatory effect of the 5-SNP block was further examined using luciferase reporter assays. FindingsWe identified a 5-SNP block located [~]556 bp upstream of the ARMS2 start codon, representing a cluster of predicted c-ABL tyrosine kinase binding sites. This block, in complete linkage disequilibrium with rs10490924 (A69S), showed a strong association with both wet and dry AMD (136 controls, 179 dry AMD, 251 wet AMD). EMSA and ChIP confirmed direct c-ABL binding, while luciferase reporter assays demonstrated reduced transcriptional activity mediated by the 5-SNP block in the presence of c-ABL. InterpretationOur results suggest that the c-ABL-responsive 5-SNP regulatory streak in the ARMS2 promoter region act as functional non-coding elements that may contribute to AMD pathogenesis through altered transcriptional regulation.

Explore related subjects

molecular biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhang, P.-W., Liu, S., Li, W., Fan, L., Li, S., Wan, Z.-H., Berlinicke, C. A., Merbs, S. L., Zack, D. J.. 2025-10-27. Identification and functional characterization of an AMD associated c-ABL binding SNP streak within the ARMS2 gene promoter region. https://doi.org/10.1101/2025.10.27.684937

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

SF3b inhibitors suppress proliferation of nonsmall cell lung cancer cells irrespective of EGFR mutation status

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard care for EGFR-mutant non-small cell lung cancer (NSCLC), but acquired resistance limits their durability, and alternatives that do not depend on EGFR kinase activity are needed. We asked whether inhibitors of SF3b, a core component of the U2 small nuclear ribonucleoprotein particle, act on NSCLC cells regardless of EGFR genotype. Three lung adenocarcinoma lines were treated with pladienolide B or herboxidiene at 0.01, 0.1 and 1 uM: PC9 and HCC827, both carrying an EGFR exon 19 deletion and both inhibited by gefitinib at nanomolar concentrations, and A549, which is EGFR wild type and gefitinibin sensitive. Proliferation was followed for three days by crystal violet staining, EGFR intron 2 retention was assayed by RTPCR, and EGFR protein was measured by western blotting. Both compounds produced a concentration-dependent increase in the intron 2 retained product in all three lines, and both held proliferation at or near the day 0 cell number in all three, at concentrations down to 0.01 uM. EGFR protein was lost in PC9, reduced in A549, and only partly reduced in HCC827, where a residual band persisted in lanes whose growth was fully suppressed. Since A549 is EGFR wild-type, and published knockdown data show that removing EGFR does not suppress proliferation of wild-type lines, the growth inhibition cannot be attributed to loss of EGFR alone. We read EGFR intron 2 retention as a marker of target engagement rather than as the mechanism of the growth effect. These are the results of single experiments without replicates or statistical testing and should be read as preliminary.

molecular biology↗
bioRxiv2026

Shared and Specific miRNA-mRNA in Human and Murine Acute Kidney Injury

Acute kidney injury (AKI) is managed as a single clinical entity despite substantial biological heterogeneity. We established a cross-species framework to define etiology-specific molecular programs and determine how these programs relate to molecular heterogeneity and pathobiology in human AKI. We performed parallel sequencing of totalRNA (mRNA) and miRNA (kidney, whole blood) in 3 murine models (mild AKI: ischemia-reperfusion injury, IRI; cecal-ligation and puncture, CLP; endotoxemia, LPS); kidney mRNA and miRNA clearly distinguished the models, blood mRNA maintained model-specific separation, and blood miRNA was less distinct. IRI was characterized by epithelial injury/repair, and extracellular matrix remodeling (i.e., miR-125b-1-3p, Vim, Sprr2g); CLP, broader inflammatory, metabolic programs (i.e., miR-692, Pfkfb3, Cdo1); LPS, inflammatory signaling (i.e., miR-155-5p, Irf7, Gbp3). We then compared these signatures to human whole blood RNAseq. Human blood samples varied along a shared gene axis that correlated to differing degrees with all three murine models, consistent with the heterogeneous nature of clinical AKI rather than discrete assignment to a single experimental etiology. Orthologs were linked to immune processes (i.e., SIGLEC14, DAAM2, CD177, DEFA3), and the presence of tubular casts in human biopsies, reflecting that mild murine AKI models capture etiology-specific biology relevant to severe human AKI. Integration of injury etiology, severity, and time may provide a framework for developing circulating biomarkers that may resolve the biological heterogeneity of human AKI.

molecular biology↗
bioRxiv2026

Distinct labeling of host and viral genomes highlights redistribution of nuclear proteins during HSV-1 infection

Herpes simplex virus type 1 (HSV-1) coordinates viral and cellular proteins during infection. While proteins associated with HSV-1 genomes have been identified, changes in proteins associated with the host genome during infection remain poorly understood. We adapted accelerated native isolation of proteins on nascent DNA (aniPOND) to label and purify cellular and viral DNA then identify associated proteins by mass spectrometry. Using this approach, we confirm observations that cellular transcription, DNA replication, and repair proteins are enriched on viral genomes after the onset of viral DNA replication. We assessed how protein interactions with cellular DNA change during infection relative to protein abundance. Targets of the viral E3 ubiquitin ligase, ICP0, are depleted from the nucleus and cellular genome during infection. Transcription regulatory factors, Pol II, and the proteasome are depleted from the host genome, while association with DNA damage response and nuclear pore proteins increases. We also provide evidence for HSV-1 disruption of ribosome biogenesis. Results demonstrate reorganization of the nucleus during infection and validate this technique to identify changes to host genome-associated factors during infection.

molecular biology↗