Jonas Paulsen

• Mirzac, Daniela; Glaser, Martin B.; Kreis, Svenja L.; Ringel, Florian; Bange, Manuel & Herz, Damian M. [Vis alle 19 forfattere av denne artikkelen] (2025). Cortical Single-Cell Primers of Abnormal Brain Activity in Parkinson’s Disease. Research. ISSN 2096-5168. 8. doi: 10.34133/research.0863. Fulltekst i vitenarkiv Vis sammendrag

  Abnormal brain oscillatory activity is a well-established hallmark of bradykinesia and motor impairment in Parkinson’s disease (PD), yet its molecular underpinnings remain unclear. To address this gap, we analyzed over 100,000 single-cell RNA transcriptomes from fresh dorsolateral prefrontal cortex tissue of individuals with PD and non-PD controls, undergoing deep brain stimulation—2 cohorts, which open up an unprecedent window to the characterization of human cortical brain tissue, aiming to uncover the molecular mechanisms of abnormal brain oscillatory activity in PD. Fresh brain tissue samples offer a unique opportunity to precisely elucidate the molecular underpinnings of known, clinically relevant electrophysiological hallmarks of neurodegeneration, which can be used to inform targeted therapeutic strategies. We depicted in microglia and astrocytes enrichment of mitochondrial electron transport and oxidative phosphorylation pathways, which were directly linked to the increase of pathological brain activity and the decrease of prokinetic brain activity. Additionally, the abnormal phase–amplitude coupling of beta–gamma brain activity was related to the dysfunction of oligodendrocyte precursor cells and inflammasome activation mediated by lymphocyte-driven adaptive immunity. We identified a distinct set of dysregulated genes from the mitogen-activated protein kinase phosphorylation pathways, mitochondrial electron transport at the intersection of neuroinflammation and neurodegeneration, suggesting pivotal roles in PD pathology. This unique dataset provides unprecedented insights into the immune and metabolic dysregulation underlying PD, offering a mechanistic framework for understanding invasive transcriptomic biomarkers related to prokinetic and pathologic brain activity in PD.

• Kumar, Vipin; Rossini, Roberto; Paulsen, Jonas & Mathelier, Anthony (2025). BHiCect 2.0: Multi-resolution clustering of Hi-C data. EarthArXiv preprint platform. doi: 10.48550/ARXIV.2512.17512. Fulltekst i vitenarkiv
• Rossini, Roberto; Oshaghi, Mohammadsaleh; Nekrasov, Maxim; Bellanger, Aurélie Nathalie Pascale; Domaschenz, Renae & Dijkwel, Yasmin [Vis alle 13 forfattere av denne artikkelen] (2025). Loss of multilevel 3D genome organization during breast cancer progression. Genome Research. ISSN 1088-9051. s. 1–18. doi: 10.1101/gr.280791.125. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we have conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that although the fundamental properties of topologically associating domains (TADs) are overall maintained, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD–TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on Chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on Chromosome 10. This insertion is accompanied by the formation of de novo enhancer contacts and activation of MYC , illustrating how structural genomic variants can alter the 3D genome during oncogenesis. In summary, our findings provide evidence for the loss of genome organization at multiple scales during breast cancer progression, revealing novel relationships between genome 3D structure and oncogenic processes.

• Patalano, Fabiana; Sandve, Simen Rød; Aasland, Rein & Paulsen, Jonas (2025). TAD conservation in vertebrate genomes is driven by stabilising selection. BMC Biology. 23(1). doi: 10.1186/s12915-025-02362-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Topologically associating domains (TADs) are fundamental structural and gene regulatory components of chromatin defined by regions of high intra-domain contact frequency. Though TADs are found across diverse metazoans, the extent of their evolutionary conservation is still debated. Results Here, we investigated the evolutionary conservation of TADs by analysing Hi-C data from 12 vertebrate species. We examined TAD numbers, borders, and gene positioning within TADs. We found that TAD features are all highly conserved across species, but decrease with evolutionary distance. Nevertheless, modelling TAD evolution using Ornstein–Uhlenbeck (OU) process revealed strong stabilising selection signatures for TAD number within the majority of syntenic blocks. These syntenic blocks under selection were enriched for highly conserved noncoding elements associated with developmental gene regulation (genomic regulatory blocks). However, strong signatures for stabilising selection for TAD numbers were also found independent of genomic regulatory blocks or genes with non-developmental functions. Conclusions These findings improve our understanding of TAD conservation and highlight stabilising selection as an important driver in 3D genome evolution. Although selection on TAD structures is pronounced for developmental genes, our findings highlight the importance of TADs in genome and organismal functions beyond developmental biology.

• Oncins, Anna; Zaurin, Roser; Toukabri, Houyem; Quililan, Kimberly; Hernández Mora, José R & Karpinska, Magdalena A [Vis alle 25 forfattere av denne artikkelen] (2025). Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(15). doi: 10.1093/nar/gkaf677. Fulltekst i vitenarkiv Vis sammendrag

  Chromosomal translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain underexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show by in vitro genomic engineering and in MCL patient samples that translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression forming pre-existing ultra-long-range interactions spanning 50 megabases. The translocation involves the strong immunoglobulin enhancer into this 3D interaction, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, by studying genome organization principles in the context of translocations, we describe a new principle of gene regulation, showing that strong enhancers can induce substantial gene expression enhancement through ultra-long-range interactions affecting entire chromosome arms, representing an important new mechanism in health and disease.

• Raffo, Andrea; Rossini, Roberto & Paulsen, Jonas (2025). StripePy: fast and robust characterization of architectural stripes. Bioinformatics. ISSN 1367-4803. 41(6). doi: 10.1093/bioinformatics/btaf351. Fulltekst i vitenarkiv Vis sammendrag

  Motivation Architectural stripes in Hi-C and related data are crucial for gene regulation, development, and DNA repair. Despite their importance, few tools exist for automatic stripe detection. Results We introduce StripePy, which leverages computational geometry methods to identify and analyze architectural stripes in contact maps from Chromosome Conformation Capture experiments like Hi-C and Micro-C. StripePy outperforms existing tools, as shown through tests on various datasets and a newly developed simulated benchmark, StripeBench, providing a valuable resource for the community. Availability and implementation StripePy is released to the public as an open-source, MIT-licensed Python application. StripePy source code is hosted on GitHub at https://github.com/paulsengroup/StripePy and is archived on Zenodo. StripePy can be easily installed from source or PyPI using pip and from Bioconda using conda. Containerized versions of StripePy are regularly published on DockerHub.

• Hovet, Oda; Nahali, Negar; Halaburkova, Andrea; Haugen, Linda Hofstad; Paulsen, Jonas & Progida, Cinzia Anita Maria (2025). Nuclear mechano-confinement induces geometry-dependent HP1α condensate alterations. Communications Biology. 8. doi: 10.1038/s42003-025-07732-6. Fulltekst i vitenarkiv Vis sammendrag

  Cells sense external physical cues through complex processes involving signaling pathways, cytoskeletal dynamics, and transcriptional regulation to coordinate a cellular response. A key emerging principle underlying such mechanoresponses is the interplay between nuclear morphology, chromatin organization, and the dynamic behavior of nuclear bodies such as HP1α condensates. Here, applying Airyscan super-resolution live cell imaging, we report a hitherto undescribed level of mechanoresponse triggered by cell confinement below their resting nuclear diameter, which elicits changes in the number, size and dynamics of HP1α nuclear condensates. Utilizing biophysical polymer models, we observe radial redistribution of HP1α condensates within the nucleus, influenced by changes in nuclear geometry. These insights shed new light on the complex relationship between external forces and changes in nuclear shape and chromatin organization in cell mechanoreception.

• Rossini, Roberto & Paulsen, Jonas (2024). hictk: blazing fast toolkit to work with .hic and .cool files. Bioinformatics. ISSN 1367-4803. 40(7). doi: 10.1093/bioinformatics/btae408. Fulltekst i vitenarkiv Vis sammendrag

  Motivation Hi-C is gaining prominence as a method for mapping genome organization. With declining sequencing costs and a growing demand for higher-resolution data, efficient tools for processing Hi-C datasets at different resolutions are crucial. Over the past decade, the .hic and Cooler file formats have become the de-facto standard to store interaction matrices produced by Hi-C experiments in binary format. Interoperability issues make it unnecessarily difficult to convert between the two formats and to develop applications that can process each format natively. Results We developed hictk, a toolkit that can transparently operate on .hic and .cool files with excellent performance. The toolkit is written in C++ and consists of a C++ library with Python and R bindings as well as CLI tools to perform common operations directly from the shell, including converting between .hic and .mcool formats. We benchmark the performance of hictk and compare it with other popular tools and libraries. We conclude that hictk significantly outperforms existing tools while providing the flexibility of natively working with both file formats without code duplication. Availability and implementation The hictk library, Python bindings and CLI tools are released under the MIT license as a multi-platform application available at github.com/paulsengroup/hictk. Pre-built binaries for Linux and macOS are available on bioconda. Python bindings for hictk are available on GitHub at github.com/paulsengroup/hictkpy, while R bindings are available on GitHub at github.com/paulsengroup/hictkR.

• Nahali, Negar; Oshaghi, Mohammadsaleh & Paulsen, Jonas (2024). Modeling properties of chromosome territories using polymer filaments in diverse confinement geometries. Chromosome Research. ISSN 0967-3849. 32. doi: 10.1007/s10577-024-09753-z. Fulltekst i vitenarkiv Vis sammendrag

  Interphase chromosomes reside within distinct nuclear regions known as chromosome territories (CTs). Recent observations from Hi-C analyses, a method mapping chromosomal interactions, have revealed varied decay in contact probabilities among different chromosomes. Our study explores the relationship between this contact decay and the particular shapes of the chromosome territories they occupy. For this, we employed molecular dynamics (MD) simulations to examine how confined polymers, resembling chromosomes, behave within different confinement geometries similar to chromosome territory boundaries. Our simulations unveil so far unreported relationships between contact probabilities and end-to-end distances varying based on different confinement geometries. These findings highlight the crucial impact of chromosome territories on shaping the larger-scale properties of 3D genome organization. They emphasize the intrinsic connection between the shapes of these territories and the contact behaviors exhibited by chromosomes. Understanding these correlations is key to accurately interpret Hi-C and microscopy data, and offers vital insights into the foundational principles governing genomic organization.

• Rossini, Roberto; Oshaghi, Mohammadsaleh; Nekrasov, Maxim; Bellanger, Aurelie Nathalie Pascale; Domaschenz, Renae & Dijkwel, Yasmin [Vis alle 10 forfattere av denne artikkelen] (2023). Multi-level 3D genome organization deteriorates during breast cancer progression. BioRxiv. ISSN 0362-4331. doi: 10.1101/2023.11.26.568711. Fulltekst i vitenarkiv
• Raffo, Andrea & Paulsen, Jonas (2023). The shape of chromatin: insights from computational recognition of geometric patterns in Hi-C data. Briefings in Bioinformatics. ISSN 1467-5463. 24(5), s. 1–14. doi: 10.1093/bib/bbad302. Fulltekst i vitenarkiv Vis sammendrag

  The three-dimensional organization of chromatin plays a crucial role in gene regulation and cellular processes like deoxyribonucleic acid (DNA) transcription, replication and repair. Hi-C and related techniques provide detailed views of spatial proximities within the nucleus. However, data analysis is challenging partially due to a lack of well-defined, underpinning mathematical frameworks. Recently, recognizing and analyzing geometric patterns in Hi-C data has emerged as a powerful approach. This review provides a summary of algorithms for automatic recognition and analysis of geometric patterns in Hi-C data and their correspondence with chromatin structure. We classify existing algorithms on the basis of the data representation and pattern recognition paradigm they make use of. Finally, we outline some of the challenges ahead and promising future directions.

• Rossini, Roberto; Kumar, Vipin; Mathelier, Anthony; Rognes, Torbjørn & Paulsen, Jonas (2022). MoDLE: high-performance stochastic modeling of DNA loop extrusion interactions. Genome Biology. ISSN 1465-6906. 23(1). doi: 10.1186/s13059-022-02815-7. Fulltekst i vitenarkiv Vis sammendrag

  DNA loop extrusion emerges as a key process establishing genome structure and function. We introduce MoDLE, a computational tool for fast, stochastic modeling of molecular contacts from DNA loop extrusion capable of simulating realistic contact patterns genome wide in a few minutes. MoDLE accurately simulates contact maps in concordance with existing molecular dynamics approaches and with Micro-C data and does so orders of magnitude faster than existing approaches. MoDLE runs efficiently on machines ranging from laptops to high performance computing clusters and opens up for exploratory and predictive modeling of 3D genome structure in a wide range of settings.

• Rossini, Roberto; Kumar, Vipin; Rognes, Torbjørn; Mathelier, Anthony & Paulsen, Jonas (2022). MoDLE: High-performance stochastic modeling of DNA loop extrusion interactions. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.04.13.488157. Fulltekst i vitenarkiv
• Ali, Tharvesh Moideen Liyakat; Brunet, Annaëlle; Collas, Philippe & Paulsen, Jonas (2021). TAD cliques predict key features of chromatin organization. BMC Genomics. 22(1). doi: 10.1186/s12864-021-07815-8. Fulltekst i vitenarkiv Vis sammendrag

  Background Mechanisms underlying genome 3D organization and domain formation in the mammalian nucleus are not completely understood. Multiple processes such as transcriptional compartmentalization, DNA loop extrusion and interactions with the nuclear lamina dynamically act on chromatin at multiple levels. Here, we explore long-range interaction patterns between topologically associated domains (TADs) in several cell types. Results We find that TAD long-range interactions are connected to many key features of chromatin organization, including open and closed compartments, compaction and loop extrusion processes. Domains that form large TAD cliques tend to be repressive across cell types, when comparing gene expression, LINE/SINE repeat content and chromatin subcompartments. Further, TADs in large cliques are larger in genomic size, less dense and depleted of convergent CTCF motifs, in contrast to smaller and denser TADs formed by a loop extrusion process. Conclusions Our results shed light on the organizational principles that govern repressive and active domains in the human genome.

• Stefano, Marco Di; Paulsen, Jonas; Jost, Daniel & Marti-Renom, Marc A. (2020). 4D nucleome modeling. Current Opinion in Genetics and Development. ISSN 0959-437X. 67, s. 25–32. doi: 10.1016/j.gde.2020.10.004. Fulltekst i vitenarkiv Vis sammendrag

  The intrinsic dynamic nature of chromosomes is emerging as a fundamental component in regulating DNA transcription, replication, and damage-repair among other nuclear functions. With this increased awareness, reinforced over the last ten years, many new experimental techniques, mainly based on microscopy and chromosome conformation capture, have been introduced to study the genome in space and time. Owing to the increasing complexity of these cutting-edge techniques, computational approaches have become of paramount importance to interpret, contextualize, and complement such experiments with new insights. Hence, it is becoming crucial for experimental biologists to have a clear understanding of the diverse theoretical modeling approaches available and the biological information each of them can provide.

• Paulsen, Jonas; Ali, Tharvesh Moideen Liyakat; Nekrasov, Maxim; Delbarre, Erwan; Baudement, Marie-Odile & Kurscheid, Sebastian [Vis alle 8 forfattere av denne artikkelen] (2019). Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation. Nature Genetics. ISSN 1061-4036. 51(5), s. 835–843. doi: 10.1038/s41588-019-0392-0. Fulltekst i vitenarkiv
• Briand, Nolwenn; Cahyani, Inswasti; Madsen-Østerbye, Julia-Kristina Jensen; Paulsen, Jonas; Rønningen, Torunn & Sørensen, Anita Løvstad [Vis alle 7 forfattere av denne artikkelen] (2018). Lamin A, Chromatin and FPLD2:Not ust a Peripheral Ménage-à-Trois. Frontiers in Cell and Developmental Biology. 6. doi: 10.3389/fcell.2018.00073. Fulltekst i vitenarkiv Vis sammendrag

  At the nuclear periphery, the genome is anchored to A- and B-type nuclear lamins in the form of heterochromatic lamina-associated domains. A-type lamins also associate with chromatin in the nuclear interior, away from the peripheral nuclear lamina. This nucleoplasmic lamin A environment tends to be euchromatic, suggesting distinct roles of lamin A in the regulation of gene expression in peripheral and more central regions of the nucleus. The hot-spot lamin A R482W mutation causing familial partial lipodystrophy of Dunnigan-type (FPLD2), affects lamin A association with chromatin at the nuclear periphery and in the nuclear interior, and is associated with 3-dimensional (3D) rearrangements of chromatin. Here, we highlight features of nuclear lamin association with the genome at the nuclear periphery and in the nuclear interior. We address recent data showing a rewiring of such interactions in cells from FPLD2 patients, and in adipose progenitor and induced pluripotent stem cell models of FPLD2. We discuss associated epigenetic and genome conformation changes elicited by the lamin A R482W mutation at the gene level. The findings argue that the mutation adversely impacts both global and local genome architecture throughout the nucleus space. The results, together with emerging new computational modeling tools, mark the start of a new era in our understanding of the 3D genomics of laminopathies.

• Paulsen, Jonas; Ali, Tharvesh Moideen Liyakat & Collas, Philippe (2018). Computational 3D genome modeling using Chrom3D. Nature Protocols. ISSN 1754-2189. 13(5), s. 1137–1152. doi: 10.1038/nprot.2018.009. Fulltekst i vitenarkiv
• Briand, Nolwenn; Guénantin, Anne-Claire; Jeziorowska, Dorota; Shah, Akshay; Mantecon, Matthieu & Capel, Emilie [Vis alle 12 forfattere av denne artikkelen] (2018). The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks. Human Molecular Genetics. ISSN 0964-6906. 27(8), s. 1447–1459. doi: 10.1093/hmg/ddy055. Fulltekst i vitenarkiv
• Garcia-Nieto, Pablo E; Schwartz, Erin K; King, Devin A; Paulsen, Jonas; Collas, Philippe & Herrera, Rafael E [Vis alle 7 forfattere av denne artikkelen] (2017). Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis. EMBO Journal. ISSN 0261-4189. 36(19), s. 2829–2843. doi: 10.15252/embj.201796717. Fulltekst i vitenarkiv
• Paulsen, Jonas; Sekelja, Monika; Oldenburg, Anja; Barateau, Alice; Briand, Nolwenn & Delbarre, Erwan [Vis alle 11 forfattere av denne artikkelen] (2017). Chrom3D: Three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts. Genome Biology. ISSN 1465-6906. 18:21, s. 1–15. doi: 10.1186/s13059-016-1146-2. Fulltekst i vitenarkiv Vis sammendrag

  Current three-dimensional (3D) genome modeling platforms are limited by their inability to account for radial placement of loci in the nucleus. We present Chrom3D, a user-friendly whole-genome 3D computational modeling framework that simulates positions of topologically-associated domains (TADs) relative to each other and to the nuclear periphery. Chrom3D integrates chromosome conformation capture (Hi-C) and lamin-associated domain (LAD) datasets to generate structure ensembles that recapitulate radial distributions of TADs detected in single cells. Chrom3D reveals unexpected spatial features of LAD regulation in cells from patients with a laminopathy-causing lamin mutation. Chrom3D is freely available on github.

• Sekelja, Monika; Paulsen, Jonas & Collas, Philippe (2016). 4D nucleomes in single cells: What can computational modeling reveal about spatial chromatin conformation? Genome Biology. ISSN 1465-6906. 17:54. doi: 10.1186/s13059-016-0923-2. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide sequencing technologies enable investigations of the structural properties of the genome in various spatial dimensions. Here, we review computational techniques developed to model the three-dimensional genome in single cells versus ensembles of cells and assess their underlying assumptions. We further address approaches to study the spatio-temporal aspects of genome organization from single-cell data.

• Stefano, Marco Di; Paulsen, Jonas; Lien, Tonje Gulbrandsen; Hovig, Johannes Eivind & Micheletti, Cristian (2016). Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization. Scientific Reports. 6. doi: 10.1038/srep35985. Fulltekst i vitenarkiv
• Børnich, Claus; Grytten, Ivar; Hovig, Johannes Eivind; Paulsen, Jonas; Cech, Martin & Sandve, Geir Kjetil (2016). Galaxy Portal: Interacting with the galaxy platform through mobile devices. Bioinformatics. ISSN 1367-4803. 32(11), s. 1743–1745. doi: 10.1093/bioinformatics/btw042. Fulltekst i vitenarkiv
• Paulsen, Jonas; Gramstad, Odin & Collas, Philippe (2015). Manifold Based Optimization for Single-Cell 3D Genome Reconstruction. PLoS Computational Biology. ISSN 1553-734X. 11(8). doi: 10.1371/journal.pcbi.1004396. Fulltekst i vitenarkiv Vis sammendrag

  The three-dimensional (3D) structure of the genome is important for orchestration of gene expression and cell differentiation. While mapping genomes in 3D has for a long time been elusive, recent adaptations of high-throughput sequencing to chromosome conformation capture (3C) techniques, allows for genome-wide structural characterization for the first time. However, reconstruction of "consensus" 3D genomes from 3C-based data is a challenging problem, since the data are aggregated over millions of cells. Recent single-cell adaptations to the 3C-technique, however, allow for non-aggregated structural assessment of genome structure, but data suffer from sparse and noisy interaction sampling. We present a manifold based optimization (MBO) approach for the reconstruction of 3D genome structure from chromosomal contact data. We show that MBO is able to reconstruct 3D structures based on the chromosomal contacts, imposing fewer structural violations than comparable methods. Additionally, MBO is suitable for efficient high-throughput reconstruction of large systems, such as entire genomes, allowing for comparative studies of genomic structure across cell-lines and different species.

• Håkelien, Anne-Mari; Bryne, Jan Christian; Harstad, Kristine Gjul; Lorenz, Susanne; Paulsen, Jonas & Sun, Jinchang [Vis alle 9 forfattere av denne artikkelen] (2014). The regulatory landscape of osteogenic differentiation. Stem Cells. ISSN 1066-5099. 32(10), s. 2780–2793. doi: 10.1002/stem.1759. Fulltekst i vitenarkiv
• Paulsen, Jonas; Rødland, Einar Andreas; Holden, Lars; Holden, Marit & Hovig, Johannes Eivind (2014). A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions. Nucleic Acids Research (NAR). ISSN 0305-1048. 42(18), s. e143–e143. doi: 10.1093/nar/gku738. Fulltekst i vitenarkiv Vis sammendrag

  Identification of three-dimensional (3D) interactions between regulatory elements across the genome is crucial to unravel the complex regulatory machinery that orchestrates proliferation and differentiation of cells. ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. However, determining the significance of the observed interaction frequencies in such datasets is challenging, and few methods have been proposed. Despite the fact that regions that are close in linear genomic distance have a much higher tendency to interact by chance, no methods to date are capable of taking such dependency into account. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall. Using both real and simulated data, we show that the previously proposed statistical test, based on Fisher's exact test, leads to invalid results when data are dependent on genomic distance. We also evaluate our method on previously validated cell-line specific and constitutive 3D interactions, and show that relevant interactions are significant, while avoiding over-estimating the significance of short nearby interactions.

• Paulsen, Jonas; Sandve, Geir Kjetil F.; Gundersen, Sveinung; Lien, Tonje Gulbrandsen; Trengereid, Kai & Hovig, Johannes Eivind (2014). HiBrowse: Multi-purpose statistical analysis of genome-wide chromatin 3D organization. Bioinformatics. ISSN 1367-4803. 30(11), s. 1620–1622. doi: 10.1093/bioinformatics/btu082. Fulltekst i vitenarkiv Vis sammendrag

  Recently developed methods that couple next-generation sequencing with chromosome conformation capture-based techniques, such as Hi-C and ChIA-PET, allow for characterization of genome-wide chromatin 3D structure. Understanding the organization of chromatin in three dimensions is a crucial next step in the unraveling of global gene regulation, and methods for analyzing such data are needed. We have developed HiBrowse, a user-friendly web-tool consisting of a range of hypothesis-based and descriptive statistics, using realistic assumptions in null-models.

• Sandve, Geir Kjetil; Gundersen, Sveinung; Johansen, Morten; Glad, Ingrid Kristine; Gunathasan, Krishanthi & Holden, Lars [Vis alle 21 forfattere av denne artikkelen] (2013). The Genomic HyperBrowser: an analysis web server for genome-scale data. Nucleic Acids Research (NAR). ISSN 0305-1048. 41(W1), s. W133–W141. doi: 10.1093/nar/gkt342. Fulltekst i vitenarkiv Vis sammendrag

  The immense increase in availability of genomic scale datasets, such as those provided by the ENCODE and Roadmap Epigenomics projects, presents unprecedented opportunities for individual researchers to pose novel falsifiable biological questions. With this opportunity, however, researchers are faced with the challenge of how to best analyze and interpret their genome-scale datasets. A powerful way of representing genome-scale data is as feature-specific coordinates relative to reference genome assemblies, i.e. as genomic tracks. The Genomic HyperBrowser (http://hyperbrowser.uio.no) is an open-ended web server for the analysis of genomic track data. Through the provision of several highly customizable components for processing and statistical analysis of genomic tracks, the HyperBrowser opens for a range of genomic investigations, related to, e.g., gene regulation, disease association or epigenetic modifications of the genome.

• Paulsen, Jonas; Lien, Tonje Gulbrandsen; Sandve, Geir Kjetil; Holden, Lars; Borgan, Ørnulf & Glad, Ingrid Kristine [Vis alle 7 forfattere av denne artikkelen] (2013). Handling realistic assumptions in hypothesis testing of 3D co-localization of genomic elements. Nucleic Acids Research (NAR). ISSN 0305-1048. 41(10), s. 5164–5174. doi: 10.1093/nar/gkt227. Fulltekst i vitenarkiv Vis sammendrag

  The study of chromatin 3D structure has recently gained much focus owing to novel techniques for detecting genome-wide chromatin contacts using next-generation sequencing. A deeper understanding of the architecture of the DNA inside the nucleus is crucial for gaining insight into fundamental processes such as transcriptional regulation, genome dynamics and genome stability. Chromatin conformation capture-based methods, such as Hi-C and ChIA-PET, are now paving the way for routine genome-wide studies of chromatin 3D structure in a range of organisms and tissues. However, appropriate methods for analyzing such data are lacking. Here, we propose a hypothesis test and an enrichment score of 3D co-localization of genomic elements that handles intra- or interchromosomal interactions, both separately and jointly, and that adjusts for biases caused by structural dependencies in the 3D data. We show that maintaining structural properties during resampling is essential to obtain valid estimation of P-values. We apply the method on chromatin states and a set of mutated regions in leukemia cells, and find significant co-localization of these elements, with varying enrichment scores, supporting the role of chromatin 3D structure in shaping the landscape of somatic mutations in cancer.

• Nordstrand, Line Mari; Furu, Kari; Paulsen, Jonas; Rognes, Torbjørn & Klungland, Arne (2012). Alkbh1 and Tzfp repress a non-repeat piRNA cluster in pachytene spermatocytes. Nucleic Acids Research (NAR). ISSN 0305-1048. 40(21), s. 10950–10963. doi: 10.1093/nar/gks839. Fulltekst i vitenarkiv Vis sammendrag

  Piwi proteins and Piwi-interacting small RNAs (piRNAs) have known functions in transposon silencing in the male germline of fetal and newborn mice. Both are also present in adult testes; however, their function here remains a mystery. Here, we confirm that most piRNAs in meiotic spermatocytes originate from clusters in non-repeat intergenic regions of DNA. The regulation of these piRNA clusters, including the processing of the precursor transcripts into individual piRNAs, is accomplished through mostly unknown processes. We present a possible regulatory mechanism for one such cluster, named cluster 1082B, located on chromosome 7 in the mouse genome. The 1082B precursor transcript and its 788 unique piRNAs are repressed by the Alkbh1 dioxygenase and the testis-specific transcription repressor Tzfp. We observe a remarkable >1000-fold upregulation of individual piRNAs in pachytene spermatocytes isolated from Alkbh1- and Tzfp -deficient murine testes. Repression of cluster 1082B is further supported by the identification of a 10-bp Tzfp recognition sequence contained within the precursor transcript. Downregulation of LINE1 and IAP transcripts in the Alkbh1- and Tzfp -deficient mice leads us to propose a potential role for the 1082B-encoded piRNAs in transposon control.

Se alle arbeider i NVA

• Årbogen, Sara Beate Stjern; Sikorski, Pawel; Paulsen, Jonas & Progida, Cinzia (2026). Investigating the Connection Between Surface Topography, Cell Membrane and Nucleus Deformation and its Impact on Chromatin Organization. Fulltekst i vitenarkiv Vis sammendrag

  The field of mechanobiology explores how physical forces and mechanical properties of cells and tissues impact cell development and cell differentiation in health and disease. Physical forces acting on the cell can lead to perturbation of the cell membrane, causing remodeling of the cytoskeleton which can result in reorganization of the nuclear morphology. This is often associated with chromatin reorganization and changes in gene expression. Unraveling the mechanism of mechanical signaling is challenging because it is difficult to study in a controlled manner. Nanofabrication methods enable the generation of precisely engineered surfaces. When combined with advanced microscopy techniques, they can facilitate controlled and systematic studies of the relationships between mechanical forces, nuclear deformation, and chromatin organization. To achieve this we fabricate nanopillar arrays on glass cover slips using electron beam lithography. Using our sample design we can test three variations of the same parameterer within a single experiment, alongside a flat control region for comparison. By seeding cells onto the substrate and allowing them to adhere, we can observe how their interaction with the nanopillars alters nuclear morphology and chromatin organization through advanced microscopy techniques. We will assess the changes in nuclear morphology and look at changes in HP1-α aggregates in the nucleus, which are proteins that are involved in compaction of chromatin.

• Årbogen, Sara Beate Stjern; Sikorski, Pawel; Paulsen, Jonas & Progida, Cinzia (2025). Investigating the Connection Between Surface Topography, Cell Membrane and Nucleus Deformation and its Impact on Chromatin Organization and Gene Expression. Fulltekst i vitenarkiv Vis sammendrag

  Changes in nuclear mechanics and shape are both considered hallmarks of disease, including cancer. Abnormal nuclear shape is linked with chromatin reorganization, and impacts gene expression. Physical forces that act on the cell can trigger remodelling of the cell cytoskeleton, which in turn can alter the nuclear shape. Knowledge of the relationship between nuclear deformation, chromatin reorganization and gene expression can be exploited for many application within biomedical research. However, revealing these relationships are challenging because it is difficult to study in a controlled manner. We address this challenge using nanofarbication methods to make substrates for cells to induce nuclear deformation, coupled with readouts on DNA condensation and gene expression.

• Årbogen, Sara Beate Stjern; Sikorski, Pawel; Paulsen, Jonas & Progida, Cinzia (2025). Investigating the Connection Between Surface Topography, Cell Membrane and Nucleus Deformation and its Impact on Chromatin Organization and Gene Expression. Fulltekst i vitenarkiv Vis sammendrag

  Changes in nuclear mechanics and shape are both considered hallmarks of disease, including cancer. Abnormal nuclear shape is linked with chromatin reorganization, and impacts gene expression. Physical forces that act on the cell can trigger remodelling of the cell cytoskeleton, which in turn can alter the nuclear shape. Knowledge of the relationship between nuclear deformation, chromatin reorganization and gene expression can be exploited for many application within biomedical research. However, revealing these relationships are challenging because it is difficult to study in a controlled manner. We address this challenge using nanofarbication methods to make substrates for cells to induce nuclear deformation, coupled with readouts on DNA condensation and gene expression.

• Rounge, Trine Ballestad & Paulsen, Jonas (2025). Highly sensitive method captures rare RNAs in blood to search for disease. Nature. ISSN 0028-0836. 641(8063), s. 599–600. doi: 10.1038/d41586-025-01127-7. Fulltekst i vitenarkiv
• Paulsen, Jonas (2025). Multi-level alterations in 3D genome organization and enhancer regulation during breast cancer progression. Fulltekst i vitenarkiv
• Paulsen, Jonas & Hovet, Oda (2024). Cell nuclei deformation impacts heterochromatin condensate structures in human cell lines. Fulltekst i vitenarkiv
• Paulsen, Jonas (2024). Modeling 3D genome organization: Implications for mutagenesis and carcinogenesis. Fulltekst i vitenarkiv
• Paulsen, Jonas (2024). Deciphering the interplay between 3D genome organization, cancer progression, and nuclear mechanoresponse. Fulltekst i vitenarkiv
• Oshaghi, Mohammadsaleh & Paulsen, Jonas (2024). Multiomic and multi-constraint modeling of cells subjected to mechano-confinement. Fulltekst i vitenarkiv
• Hovet, Oda & Paulsen, Jonas (2023). Investigating nuclear deformation and the role of HP1alpha upon confinement. Fulltekst i vitenarkiv
• Paulsen, Jonas & Patalano, Fabiana (2023). Comparing Synteny and 3D Chromatin Architecture: Insights into structure evolutionary patterns and speciation in vertebrates. Fulltekst i vitenarkiv
• Nahali, Negar & Paulsen, Jonas (2023). Association of flexible filaments under different confinement geometries. Fulltekst i vitenarkiv
• Paulsen, Jonas (2023). Modeling loop extrusion dynamics genome wide. Fulltekst i vitenarkiv
• Raffo, Andrea & Paulsen, Jonas (2023). Towards a fast and robust characterization of TAD border stripes. Fulltekst i vitenarkiv
• Paulsen, Jonas (2022). Genomet er som et flokete nøste. [Journal]. Bioingeniøren. Fulltekst i vitenarkiv
• Paulsen, Jonas (2022). Loops and loopholes in 3D genome modeling. Fulltekst i vitenarkiv
• Paulsen, Jonas & Collas, Philippe (2022). Modeling the 3D Genome Using Hi-C and Nuclear Lamin-Genome Contacts. I Bicciato, Silvio & Ferrari, Francesco (Red.), Hi-C Data Analysis Methods and Protocols. Humana Press. ISSN 9781071613900. s. 337–352. doi: 10.1007/978-1-0716-1390-0_18. Fulltekst i vitenarkiv
• Star, Bastiaan; Nederbragt, Alexander Johan; Jentoft, Sissel; Grimholt, Unni; Malmstrøm, Martin & Gregers, Tone Fredsvik [Vis alle 18 forfattere av denne artikkelen] (2011). The genome of Atlantic cod reveals a unique immune system. Fulltekst i vitenarkiv
• Paulsen, Jonas (2014). Inferential analysis of genomic 3D organization. Universitetet i Oslo. Fulltekst i vitenarkiv Vis sammendrag

  DNA inside the nuclei of cells is folded into an intricate three-dimensional (3D) structure that influences how and when genes are turned on and off. For example, 3D interactions between distal regulatory elements, such as enhancers and their promoter targets are known to be responsible for regulating a range of genes with cell-type specific functions. Recent technologies coupling chromosome conformation capture to next-generation sequencing, such as Hi-C and ChIA-PET, allow for genome-wide identification of 3D interactions at unprecedented resolution. However, analysis is challenging due to the complexity of the data. This PhD-thesis presents several statistical models and computational tools to analyze such data, based on realistic assumptions regarding the underlying properties of chromatin structure. The thesis presents a model for analysis of 3D co-localization of selected elements in the genome. Additionally, the thesis presents a web-based analysis server called HiBrowse (https://hyperbrowser.uio.no/3d/), for performing statistical analysis of 3D genomes in a range of different settings. Finally, the thesis presents a statistical model for ChIA-PET data, allowing for accurate identification of significant interactions between regulatory regions in the genome.

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