SAT-256 - Integrative in silico evidence for a VDR/RXR-responsive cis-regulatory module at the PM20D1 locus in human skin

Background: Skin, particularly the sebaceous unit, is an endocrine-metabolic compartment that integrates hormonal, inflammatory, and lipid cues, yet downstream effectors of vitamin D signaling relevant to metabolic regulation remain incompletely defined. PM20D1 encodes a secreted enzyme that controls N-acyl amino acid biosynthesis and turnover, linking lipid metabolism to energy expenditure, glucose homeostasis, and nociceptive signaling. We tested whether PM20D1 is a direct cutaneous target of the VDR/RXR axis.

Methods: We applied an integrated in silico workflow combining FIMO/MEME scanning of the 5-kb PM20D1 promoter, AlphaFold-based modeling of VDR/RXR DNA-binding domains, HDOCK/HADDOCK protein-DNA docking, Ensembl VEP annotation, GTEx skin eQTL interrogation, LD mapping, and ENCODE/Roadmap chromatin analysis.

Results: Four VDRE-like motifs were identified in the proximal promoter. A 21-bp element supported stable and energetically favorable VDR/RXR-DNA binding, with major-groove recognition and geometry consistent with a DR3-type arrangement (~29 Å between recognition centers; HADDOCK score -133.4±8.4, refined -121.9±9.7). At the genetic level, rs1104899 (p.Arg153Trp) showed predicted functional relevance (SIFT 0.04; PolyPhen-2 0.961; CADD 23; REVEL 0.408) and acted as an eQTL for PM20D1 in sun-unexposed skin (NES +0.16; P=1.1×10-5). LD analysis prioritized rs12028467, a distal noncoding proxy (~40 kb from PM20D1) with strong regulatory evidence (RegulomeDB 1b), enhancer-like chromatin features (H3K27ac/DNase), and predicted disruption of transcription factor motifs, including NF-κB-related sites.

Conclusions: These convergent findings support a persuasive, testable model in which vitamin D signaling directly regulates PM20D1 in skin, connecting VDR/RXR activity to N-acyl amino acid biology and potentially to systemic endocrine-metabolic phenotypes. The key remaining gaps are causal validation in sebocytes/keratinocytes, allele-specific enhancer testing, and proof that cutaneous PM20D1 modulation changes N-acyl amino acid output and systemic physiology.

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