Search bioRxiv⌕ Search

bioRxiv · 10.1101/396457

Computations performed by shadow enhancers and enhancer duplications vary across the Drosophila embryo

Abstract

Transcription of developmental genes is controlled by multiple enhancers. Frequently, more than one enhancer can activate transcription from the same promoter in the same cells. In these cases, how is regulatory information from multiple enhancers combined to determine the overall expression output of their shared promoter? To investigate this question, we quantified nascent transcription driven by a pair shadow enhancers, each individual of the pair, and their duplications in Drosophila embryos using live imaging. This set of constructs allows us to quantify the \"computation\" made by the pairs of enhancers: their combined output expression as a function of the expression that they drive separately. We show that the computation performed by these shadow enhancers and duplications varies across the expression pattern, implying that how their activities are combined depends on the transcriptional regulators bound to the enhancers in different parts of the embryo. Characterizing the computation made by multiple enhancers is a critical first step in developing conceptual and computational models of gene expression at the locus level, where multiple enhancers collaborate.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Scholes, C., Biette, K. M., Harden, T. T., DePace, A. H.. 2018-08-20. Computations performed by shadow enhancers and enhancer duplications vary across the Drosophila embryo. https://doi.org/10.1101/396457

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

KEEP EXPLORING

Related preprints

Uncovering disease progression trajectories across multiple timescales with hybrid ODE-mixture models

Biological systems are capable of evolving across multiple timescales, yet most modeling approaches capture either short-term physiological responses or long-term disease progression. Additionally, methods that combine these time scales either struggle with inter-individual variation, or require large volumes of data to work. We present Latent Class Parameter Trajectory Analysis (LCPTA), a hybrid framework that combines mechanistic ordinary differential equation (ODE) modeling of short-term dynamics with latent class trajectory modeling of long-term parameter evolution. To support this approach, we developed TemporalMixtureModels.jl, a Julia package for univariate and multivariate temporal mixture modeling. We evaluated LCPTA in two synthetic longitudinal studies, covering a simulation of a heterogeneous population developing hypertension, as well as a synthetic longitudinal study of 75 virtual individuals followed over 30 years, representing muscle insulin resistance, liver insulin resistance, and healthy trajectories. We compared LCPTA with a conditional neural ODE and a conditional neural network for reconstruction of long-term parameter trajectories and subgroup separation. In both studies LCPTA recovered relevant subgroup structure and trajectory patterns. In the cardiovascular study, the neural approaches were able to distinguish inter-individual differences, but in the insulin sensitivity study, neural approaches failed to represent parameter trajectories faithfully, primarily separating individuals along a single dominant parameter and showing weaker multivariate trajectory reconstruction. In additional experiments with sparse and irregularly sampled unseen individuals, LCPTA maintained strong classification performance. We show that LCPTA is an efficient and interpretable strategy for multiscale modeling of heterogeneous metabolic disease progression, with potential utility for data-efficient digital twin applications.

systems biology↗

The Global Phosphorylation Landscape of Acute Heat Stress in Reef-Building Corals

Warming oceans disrupt the coral-algal symbiosis that sustains reefs, yet the signaling mechanisms initiating bleaching remain poorly understood. Integrating global phosphoproteomics across three reef-building corals with protein structure modeling revealed conservation between coral and human kinases, enabling inference of coral kinase activities and uncovering a shared signaling program induced by acute heat stress. Heat rapidly activated ERK, JNK, and p38 MAP kinases, suppressed cell cycle signaling, and remodeled pathways controlling chromatin, RNA processing, and metabolism. Most strikingly, thermal stress rewired immune receptor signaling networks associated with non-self recognition, suggesting that heat shifts the coral host from tolerance to immune recognition of its algal symbionts. These findings define conserved signaling mechanisms that precede bleaching, revealing actionable molecular targets for enhancing coral resilience.

systems biology↗

Estimating glioblastoma migration-to-proliferation ratio from single time-point MRI data via radial density distribution

Glioblastoma (GBM) tumors with a high migration-to-proliferation ratio (D/k) are associated with treatment resistance, motivating the estimation of D/k from routine pre-treatment magnetic resonance imaging (MRI) data and the investigation of mechanisms underlying its heterogeneity across patients. Unlike previous approaches based on nested spherical approximations of enhancing and non-enhancing tumor volumes, we incorporate the spatial arrangement of the enhancing and non-enhancing tumor regions by deriving a 1D tumor density distribution from their segmentations and fitting a 1D reaction-diffusion model to estimate D/k. We achieved an error of under 5% when comparing our method to synthetic density distributions and found excellent correlation with synthetic tumor segmentations (Pearson correlation coefficient (PCC) = 0.996). We then evaluated associations between patient-specific D/k values and their clinical, transcriptomic, and radiomic features. When applied to 102 pre-treatment MRI scans from the Brain Tumor Segmentation (BraTS) 2017 dataset, elevated D/k significantly correlated with reduced overall survival (log-rank p = 0.01), older age (p = 0.04), and a trend toward lower Karnofsky Performance Status (p = 0.059). In a subset of 91 patients with available microarray data, mesenchymal-like phenotypes consistently exhibited elevated D/k across three established molecular subtype classifications (p = 0.013, p = 0.055, and p = 0.127). Elastic Net regularization followed by overrepresentation analysis revealed an enrichment of glycosylation-related pathways among genes associated with D/k variability (p = 0.0123 and p = 0.0368). Furthermore, Multi-Omic Factor Analysis identified a radiomic factor correlated with D/k (r = 0.57, p = 4x10-9), with the highest-weighted features corresponding to smoothness of the non-enhancing tumor region on T2 and FLAIR.

systems biology↗