Paulsen group

Computational 3D genomics

The focus of the group is to understand how the three-dimensional (3D) organization of DNA inside the nucleus relates to critical functions in the eukaryotic cell, such as gene expression regulation and the cell cycle. We use computational modeling, statistical analyses and machine learning to elucidate evolutionary trajectories and functional relationships across cell-types, tissues and species.

Image may contain: Sphere.

Research projects

A central technology in the group is the Hi-C technique. We build computational tools to analyze these and related data, to increase our understanding of the eukaryotic genome. Below, are some recent (and ongoing) projects.

Chrom3D – Three-dimensional genome modeling from Hi-C data

Chrom3D is our genome 3D modeling platform – designed to integrate Hi-C data with other positional constraints based on association of loci with intranuclear anchors. The combination of Hi-C and other information enables genome-wide radial positioning of TADs in ensembles of 3D structures. In several ongoing projects, Chrom3D is consistently maintained and developed further. Chrom3D is available on Github: https://github.com/Chrom3D/Chrom3D

Further reading:
– Paulsen et al. (2017). Chrom3D: three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts. Genome Biology
– Paulsen et al. (2018). Computational 3D modeling using Chrom3D. Nature Protocols.

Statistical models of genome contact frequency maps

We are developing statistical models of contact frequency maps from single-cell (and ensemble) Hi-C, ChIA-PET and related data. These statistical models allow us to explore the data in new ways, to learn about the underlying properties of genome organization. For example, we have determined a set of intrinsic structural principles giving rise to correlations between distal genomic regions. These need to be accounted for during inferential analysis from these contact maps. Further, we have developed models that allow us to directly infer 3D structural models of chromosomes from single-cell Hi-C data.

Further reading:
– Paulsen et al. (2015) Manifold based optimization for single-cell 3D genome reconstruction. PLOS Computational Biology
– Paulsen et al. (2013) Handling realistic assumptions in hypothesis testing of 3D co-localization of genomic elements. Nucleic Acids Research
– Sekelja et al. (2016) 4D nucleomes in single cells: what can computational modeling reveal about spatial chromatin conformation? Genome Biology

Genome domains: understanding their functional and evolutionary basis

Eukaryotic genomes are non-randomly organized. Even though the mechanisms underlying genome structure regulation can vary across species, some general “rules” related to gene expression differences seem to apply. Most species organize their chromosomes into separate territories within the nucleus, and within the chromosomes different regions are usually organized into compartments and/or domains. In mammals, Topologically Associated Domains (TADs) is a prominent feature seen along the diagonal of the Hi-C contact matrices (see images above). Many of these TADs seem to be formed by a proposed process termed Loop extrusion. Together with Philippe Collas, we have identified a subset of TADs (TAD-cliques) behaving similar to compartments, yet with distinct features. These TADs are altered during differentiation in concert with formation of heterochromatin compartments in the nuclear periphery. 

Further reading:
– Paulsen et al. (2019) Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation. Nature Genetics

Other projects

We are interested in a range of other genomics topics as well, and are always interested in collaborating with groups that work with these (and related) topics:

  • Genome assembly. Especially using Hi-C assisted approaches
  • Epigenetics and gene regulation
  • Somatic mutations in cancer and other diseases
  • We can also help with development of bioinformatics tools/software

 

The group was established in early 2020, and is affiliated with Centre for Bioinformatics, and Section for Genetics and Evolutionary Biology.

Publications

Publications 2019

Paulsen J, Liyakat Ali TM, Nekrasov M, Delbarre E, Baudement MO, Kurscheid S, Tremethick D, Collas P (2019)
Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation
Nat Genet, 51 (5), 835-843
DOI 10.1038/s41588-019-0392-0, PubMed 31011212

Publications 2018

Briand N, Cahyani I, Madsen-Østerbye J, Paulsen J, Rønningen T, Sørensen AL, Collas P (2018)
Lamin A, Chromatin and FPLD2: Not Just a Peripheral Ménage-à-Trois
Front Cell Dev Biol, 6, 73
DOI 10.3389/fcell.2018.00073, PubMed 30057899

Paulsen J, Liyakat Ali TM, Collas P (2018)
Computational 3D genome modeling using Chrom3D
Nat Protoc, 13 (5), 1137-1152
DOI 10.1038/nprot.2018.009, PubMed 29700484

Briand N, Guénantin AC, Jeziorowska D, Shah A, Mantecon M, Capel E, Garcia M, Oldenburg A, Paulsen J, Hulot JS, Vigouroux C, Collas P (2018)
The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks
Hum Mol Genet, 27 (8), 1447-1459
DOI 10.1093/hmg/ddy055, PubMed 29438482

Publications 2017

García-Nieto PE, Schwartz EK, King DA, Paulsen J, Collas P, Herrera RE, Morrison AJ (2017)
Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis
EMBO J, 36 (19), 2829-2843
DOI 10.15252/embj.201796717, PubMed 28814448

Paulsen J, Sekelja M, Oldenburg AR, Barateau A, Briand N, Delbarre E, Shah A, Sørensen AL, Vigouroux C, Buendia B, Collas P (2017)
Chrom3D: three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts
Genome Biol, 18 (1), 21
DOI 10.1186/s13059-016-1146-2, PubMed 28137286

Publications 2016

Di Stefano M, Paulsen J, Lien TG, Hovig E, Micheletti C (2016)
Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization
Sci Rep, 6, 35985
DOI 10.1038/srep35985, PubMed 27786255

Sekelja M, Paulsen J, Collas P (2016)
4D nucleomes in single cells: what can computational modeling reveal about spatial chromatin conformation?
Genome Biol, 17, 54
DOI 10.1186/s13059-016-0923-2, PubMed 27052789

Børnich C, Grytten I, Hovig E, Paulsen J, Čech M, Sandve GK (2016)
Galaxy Portal: interacting with the galaxy platform through mobile devices
Bioinformatics, 32 (11), 1743-5
DOI 10.1093/bioinformatics/btw042, PubMed 26819474

Publications 2015

Paulsen J, Gramstad O, Collas P (2015)
Manifold Based Optimization for Single-Cell 3D Genome Reconstruction
PLoS Comput Biol, 11 (8), e1004396
DOI 10.1371/journal.pcbi.1004396, PubMed 26262780

Publications 2013

Sandve GK, Gundersen S, Johansen M, Glad IK, Gunathasan K, Holden L, Holden M, Liestøl K, Nygård S, Nygaard V, Paulsen J, Rydbeck H, Trengereid K, Clancy T, Drabløs F, Ferkingstad E, Kalas M, Lien T, Rye MB, Frigessi A, Hovig E (2013)
The Genomic HyperBrowser: an analysis web server for genome-scale data
Nucleic Acids Res, 41 (Web Server issue), W133-41
DOI 10.1093/nar/gkt342, PubMed 23632163

Publications 2011

Star B, Nederbragt AJ, Jentoft S, Grimholt U, Malmstrøm M, Gregers TF, Rounge TB, Paulsen J, Solbakken MH, Sharma A, Wetten OF, Lanzén A, Winer R, Knight J, Vogel JH, Aken B, Andersen O, Lagesen K, Tooming-Klunderud A, Edvardsen RB, Tina KG, Espelund M, Nepal C, Previti C, Karlsen BO et al. (2011)
The genome sequence of Atlantic cod reveals a unique immune system
Nature, 477 (7363), 207-10
DOI 10.1038/nature10342, PubMed 21832995

Published Feb. 17, 2020 2:44 PM - Last modified Feb. 27, 2020 11:25 AM