Graph Neural Network-Based Reinforcement Learning for Controlling Biological Networks - the GATTACA Framework

Gene regulatory networks (GRNs) capture transcription factor-target interactions and are central to understanding cell-state regulation and disease. Reconstructing GRNs from paired single-cell transcriptomic and chromatin accessibility data is promising but challenging: scATAC is extremely sparse, and most methods rely on fixed peak-to-gene links and weak supervision. We present EpiAwareNet, a prior-guided multi-omic Transformer framework that reconstructs GRNs from paired single-cell data using only lightweight biological priors. In Stage 1, EpiAwareNet learns joint gene-peak representations with a gene-peak cross-attention module, enabling data-driven, gene-specific aggregation of accessibility signals rather than hard-coded peak-to-gene assignments. In Stage 2, EpiAwareNet incorporates a bulk-derived GRN prior as noisy positive edges to provide weak supervision under label scarcity, refining regulatory scores while remaining robust to prior noise. In our experiments, EpiAwareNet improves GRN reconstruction over representative single- and multi-omic baselines and yields GRNs with greater biological plausibility, such as improved recovery of known regulatory interactions, suggesting that lightweight biological priors from bulk data can effectively guide single-cell GRN inference when combined with adaptive cross-modal representation learning. Code and data will be available at https://github.com/tianyang-x/EpiAwareNet_pub.

Biological foundation models have shown strong performance in single-cell representation learning by applying transformer architectures directly to gene-expression matrices. However, these approaches predominantly operate in static settings and do not explicitly model the temporal evolution of developmental programs in the cell. Modeling such dynamics is important for understanding how cellular states progressively emerge, differentiate, and reorganize during development or disease progression. In this work-in-progress paper, we investigate an alternative temporal graph-based perspective in which cellular states are represented through pseudotime-resolved gene regulatory networks and modeled as evolving graph structures over persistent gene identities. Starting from single-cell transcriptomic data, we infer pseudotime trajectories, discretize cells into developmental snapshots, reconstruct one gene regulatory network per snapshot, and apply temporal graph neural networks to forecast biological states. We evaluate this framework on two publicly available mouse developmental datasets, erythroid gastrulation and pancreatic endocrinogenesis, considering three complementary tasks: gene-expression forecasting, link prediction, and out-degree centrality prediction. Our results show that graph-based models outperform well-known foundation-model such as scGPT and scFoundation, suggesting that explicitly modeling evolving regulatory structure provides useful information beyond static pretrained representations. For link prediction and centrality forecasting, temporal graph learning captures non-trivial regulatory dynamics and enables the identification of temporally important gene hubs. Overall, our findings support temporal graph learning as a promising direction for modeling dynamic biological systems and as a complementary paradigm to current foundation model approaches in single-cell biology.

Building virtual cells with generative models to simulate cellular behavior in silico is emerging as a promising paradigm for accelerating drug discovery. However, prior image-based generative approaches can produce implausible cell images that violate basic physical and biological constraints. To address this, we propose to post-train virtual cell models with reinforcement learning (RL), leveraging biologically meaningful evaluators as reward functions. We design seven rewards spanning three categories-biological function, structural validity, and morphological correctness-and optimize the state-of-the-art CellFlux model to yield CellFluxRL. CellFluxRL consistently improves over CellFlux across all rewards, with further performance boosts from test-time scaling. Overall, our results present a virtual cell modeling framework that enforces physically-based constraints through RL, advancing beyond "visually realistic" generations towards "biologically meaningful" ones.