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The three-dimensional (3D) organization of chromatin plays a critical role in regulating gene expression and genomic processes like DNA replication, repair, and genome stability. Although these processes occur at the individual-cell level, most chromatin structure data are derived from population-averaged assays, such as Hi-C, obscuring the heterogeneity of single-cell conformations. To address this limitation, we developed a polymer physics-based modeling framework, the sequential Bayesian inference framework (sBIF), that deconvolutes bulk Hi-C data to reconstruct single-cell 3D chromatin conformations. To support a broader use of sBIF, we created ChromPolymerDB, a publicly accessible, high-resolution database of single-cell chromatin structures inferred by sBIF. The database contains ∼108 reconstructed 5 kb-resolution single cell structures, spanning over 60,000 genomic loci across 50 human cell types and experimental conditions. ChromPolymerDB features an interactive web interface with tools for 3D structural analysis and multi-omics integration. Users can explore associations between chromatin conformation and gene expression, epigenetic modifications, and regulatory elements. The platform also supports comparative analyses to identify structural changes across cell types, developmental stages, or disease contexts. ChromPolymerDB offers a unique resource for researchers studying the relationship between genome architecture and gene regulation, and for advancing comparative 3D genomics. ChromPolymerDB is available online at https://chrompolymerdb.bme.uic.edu/.
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This content will become publicly available on March 1, 2027
EpGAT: integrating epigenetics and 3D genome structure to predict alternative splicing and polyadenylation
Abstract Understanding how the 3D structure of the genome influences gene regulation is a growing area of interest, particularly in the context of alternative post-transcriptional regulatory events such as alternative splicing (AS) and alternative polyadenylation (APA). These processes are essential for generating transcript and protein diversity, and they are tightly coordinated with transcription. However, despite their biological importance, the relationship between chromatin interactions and alternative pre-messenger RNA regulation remains poorly understood. This gap largely stems from a lack of computational tools capable of integrating structural genomic data with RNA processing dynamics. Exploring how chromatin interactions and epigenetic landscapes shape these events is essential for uncovering the multilayered regulation of gene expression. To bridge this gap, we present EpGAT, a graph attention network-based model that integrates epigenetic read coverage and chromatin interaction data to predict and quantify AS and APA events. By explicitly modeling the spatial organization of the genome, EpGAT captures the regulatory influence of chromatin looping and long-range genomic interactions on RNA processing. The model’s predictions are validated through rigorous cross-cell line and cross-chromosome evaluations, affirming its generalizability and reliability. Beyond prediction, EpGAT offers interpretability by tracing learned parameters back to genomic features, enabling the identification of active enhancers, mapping promoter–enhancer connectivity, and pinpointing the epigenetic factors most critical to specific RNA processing events. These capabilities make EpGAT a powerful tool for dissecting the complex interplay between genome architecture and transcriptomic regulation. More broadly, it provides a generalizable framework for multiple tasks to study the link between 3D genome organization, epigenetic signals, and RNA processing.
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- Award ID(s):
- 2246796
- PAR ID:
- 10683018
- Publisher / Repository:
- Oxford
- Date Published:
- Journal Name:
- Briefings in Bioinformatics
- Volume:
- 27
- Issue:
- 2
- ISSN:
- 1467-5463
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Alternative polyadenylation (APA) and alternative splicing (AS) are essential post-transcriptional mechanisms that enhance transcriptome diversity and regulate gene expression across various biological contexts. APA modifies transcript stability, localization and translation efficiency by generating mRNA isoforms with distinct 3′ untranslated regions or coding sequences, while AS alters protein diversity through exon inclusion or exclusion. The advent of high-throughput RNA sequencing has driven the development of computational methods to systematically identify, quantify and analyze APA and AS events, shedding light on their regulatory roles in normal physiology and disease. These methods can be broadly categorized based on their underlying methodologies and the data types they process, with specialized tools designed for both bulk and single-cell RNA sequencing. Here, in this Review, we provide a comprehensive overview of computational strategies for APA and AS detection and differential analysis, highlighting their advantages, limitations and applications. In addition, we explore techniques specifically tailored for single-cell RNA sequencing. We enhance our understanding of APA and AS regulation across diverse biological systems by summarizing recent advancements, offering new insights into gene regulation at both the population and single-cell levels.more » « less
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Prigent, Claude (Ed.)Alternative polyadenylation (APA) is an important contributor to the regulation of gene expression in plants. One subunit of the complex that cleaves and polyadenylates mRNAs in the nucleus, CPSF30 (for the 30 kD subunit of the mammalian Cleavage and Polyadenylation Specificity Factor), has been implicated in a wide-ranging network of regulatory events. CPSF30 plays roles in root development, flowering time, and response to biotic and abiotic stresses. CPSF30 also is a conduit that links cellular signaling and RNA modification with alternative RNA processing events and transcriptional dynamics. While much is known about CPSF30 and its roles in plants, questions remain regarding the connections between CPSF30-mediated APA and the downstream events that lead to specific phenotypic outcomes. To address these, we conducted a detailed analysis of poly(A) site usage in the CPSF30 mutant. Our results corroborate earlier reports that link CPSF30 with a distinctive cis element (AAUAAA) that is present 10-30 nts upstream of some, but not all, plant pre-mRNAs. Interestingly, our results reveal a distinctive shift in poly(A) site in mutants deficient in CPSF30, resulting in cleavage and polyadenylation at the location of motifs similar to AAUAAA. Importantly, CPSF30-associated APA had at best a small impact on mRNA functionality. These results necessitate the formulation of new hypotheses for mechanisms by which CPSF30-mediated APA influences physiological processes.more » « less
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