HoloGene: Learning to Lift Sliced Spatial Transcriptomics to Holistic 3D Gene Fields

Spatial transcriptomics (ST) provides spatially resolved gene expression measurements, but most 3D ST datasets are acquired as independently processed 2D sections. This sliced acquisition creates a difficult reconstruction problem: measurements are dense within each section but sparse along the axial direction, and inter-section technical variation can be confounded with true biological change. Existing coordinate-based implicit neural representations (INRs) provide a continuous modeling framework, but standard isotropic coordinate encodings do not explicitly reflect this axial-to-lateral imbalance. We present HoloGene, an anisotropic conditional INR framework for estimating continuous 3D gene-expression fields from pre-registered ST sections. HoloGene first compresses high-dimensional expression profiles into a graph-autoencoder latent manifold. It then uses pseudo-label-derived biological signature conditioning to provide coarse intra-section biological context, while depth-dependent FiLM modulation models axial variation. To reduce slice-specific covariance shifts, we introduce a signature-stratified correlation-alignment regularizer over latent features. Using held-out measured sections as cross-sectional references, HoloGene improves reconstruction accuracy and biological preservation metrics compared with general-purpose INRs and adapted spatial-transcriptomics baselines. Ablation analyses show that decoupled depth conditioning improves axial generalization, while correlation alignment provides the strongest reduction in slice-specific representation leakage. These results support anisotropic conditional modeling as a practical strategy for estimating continuous 3D expression fields from discontinuous ST sections.