Biology subjects

Berkemeier, F.

Publications and source records attributed to Berkemeier, F..

4 recordsLinked to original sources

bioRxiv2026

A genome language model for mapping DNA replication origins

Origin firing is a central process during DNA replication, but specific sequences defining replication origin usage have not been defined in human cells. Here, we show that a genome language model can accurately predict which sequences can act as an origin of replication, thereby enabling the fast and cost-effective creation of genome-wide replication origin maps. We fine-tuned a genome language model on the primary sequence of mapped human origins to establish ORILINX (ORIgin of replication Language-model Inference via Nucleotide conteXt) and found that it learns a rich representation of sequence features linked to replication initiation, extending beyond known predictive features such as GC-content and G-quadruplex motifs. When applied genome-wide, the models sequence-derived origin calling closely mirrors origin efficiency inferred from replication timing, suggesting that intrinsic sequence context encodes information relevant to initiation frequency. Furthermore, we performed Short Nascent Strand sequencing (SNS-seq) and Repli-seq to demonstrate that ORILINX can generalise to other mammalian genomes, such as those of mice and sheep, as well as other vertebrates such as chickens. Finally, we packaged ORILINX into a simple, easy-to-use tool which is available at https://github.com/Pfuderer/ORILINX.git.

genomics↗

bioRxiv2025

3D epithelial cell topology tunes signalling range to promote precise patterning

Cell behaviours in multicellular organisms are coordinated via both diffusible molecules and by signals based on direct cell-cell contacts. The mode of cell communication used influences the signalling range. In many developing epithelia, contact-based Notch-Delta lateral inhibition signalling is used to pattern cell fates. While previous work revealed that cells can use protrusions to extend the range of Notch-Delta signalling to alter these patterns, this is not a general feature of epithelia. In addition, it is not known how the complex three-dimensional (3D) shapes of epithelial cells influence cell communication. In exploring this question, we show that epithelial cells at the Drosophila wing margin, which lack basal protrusions, contact different neighbours at different heights along their apico-basal axis, effectively increasing the number of neighbours each cell touches. To quantitatively assess this behaviour, we develop a novel mathematical modelling framework (Multi-layer Signalling Model) to simulate Notch-Delta signalling over data-derived 3D cell topologies. The model predicts that lateral cell surface signalling is essential to tune the spacing between SOPs. In agreement, we show that perturbing cortical stiffness and cell tortuosity in vivo modifies SOP spacing. These results emphasise the importance of 3D cell geometry and topology in fine-tuning signalling range.

developmental biology↗

bioRxiv2024

DNA replication timing reveals genome-wide features of transcription and fragility

DNA replication in humans requires precise regulation to ensure accurate genome duplication and maintain genome integrity. A key indicator of this regulation is replication timing, which reflects the interplay between origin firing and fork dynamics. We present a high-resolution (1-kilobase) mathematical model that maps firing rate distributions to replication timing profiles across various cell lines, validated using Repli-seq data. The model effectively captures genome-wide replication patterns while identifying local discrepancies. Notably, regions where the model and data diverge often overlap with fragile sites and long genes, highlighting the influence of genomic architecture on replication dynamics. Conversely, regions of high concordance are associated with open chromatin and active promoters, where elevated firing rates facilitate timely fork progression and reduce replication stress. By establishing these correlations, our model provides a valuable framework for exploring the structural interplay between replication timing, transcription, and chromatin organisation, offering new insights into mechanisms underlying replication stress and its implications for genome stability and disease.

systems biology↗

bioRxiv2024

Regulation of replication timing in Saccharomyces cerevisiae

In order to maintain genomic integrity, DNA replication must be highly coordinated. Disruptions in this process can cause replication stress which is aberrant in many pathologies including cancer. Despite this, little is known about the mechanisms governing the temporal regulation of DNA replication initiation, thought to be related to the limited copy number of firing factors. Here, we present a high (1-kilobase) resolution stochastic model of Saccharomyces cerevisiae whole-genome replication in which origins compete to associate with limited firing factors. After developing an algorithm to fit this model to replication timing data, we validated the model by reproducing experimental inter-origin distances, origin efficiencies, and replication fork directionality. This suggests the model accurately simulates the aspects of DNA replication most important for determining its dynamics. We also use the model to predict measures of DNA replication dynamics which are yet to be determined experimentally and investigate the potential impacts of variations in firing factor concentrations on DNA replication.

systems biology↗