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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol.26, no.18, 2025 (SCI-Expanded)
Cortical transcriptional dysregulation is widespread in Huntington's disease (HD). We re-examined prefrontal Brodmann Area 9 (BA9) RNA-seq (GSE64810; 20 HD, 49 controls) using BH-FDR and GEO2R to obtain differential-expression statistics for downstream in silico integration. A compact, direction-aware 80-gene panel was assembled for visualization/ranking only, while inference relied on validated target sets and full-universe testing. At FDR < 0.05, we detected Up = 2923 and Down = 2448 genes (ratio 1.19), indicating a mild predominance of up-regulation. MIR219A2 was strongly down-regulated, and four experimentally validated targets (FOXC1, NFKBIA, SLC38A2, SLC6A20) overlapped the up-regulated core; as expected for n = 4, no GO/KEGG/Reactome term met FDR < 0.05, and STRING returned no high-confidence edges. Beyond the curated panel, we tested MIR219A2 (hsa-miR-219a-5p; hsa-miR-219a-1-3p; hsa-miR-219a-2-3p) targets against the full FDR-significant BA9 up-regulated universe. Two orthogonal, experimentally supported resources-miRTarBase functional assays and ENCORI/starBase CLIP-showed direction-consistent, FDR-controlled enrichment, with effect sizes and uncertainty reported in the main text, supporting a BA9-specific, MIR219A2-aligned association signal. On the TF axis, MSigDB C3:TFT (gene symbols) revealed significant over-representation of TF target sets among BA9-Up under the same BA9 expressed-gene background after BH-FDR (e.g., NFAT motifs, C/EBP, FOXA/HNF3), while TRRUST v2 applied to the MIR219A2 CLIP-BA9-Up subset provided target-level transparency. MIR219A2 enrichments were robust to composition sensitivity analyses (marker-excluded and neuron/glia-stratified backgrounds). Exploratory GO-Biological Process bubbles are shown for trend summarization only; no term met FDR < 0.05 in the primary analysis. All conclusions are analysis-only; no wet-lab or biofluid/peripheral assays were performed, and findings are BA9-specific-generalization to other regions remains hypothesis-generating.