umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Publications (5 of 5) Show all publications
Kumar, R., Lizana, L. & Stenberg, P. (2019). Genomic 3D compartments emerge from unfolding mitotic chromosomes. Chromosoma, 128(1), 15-20
Open this publication in new window or tab >>Genomic 3D compartments emerge from unfolding mitotic chromosomes
2019 (English)In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 128, no 1, p. 15-20Article in journal (Refereed) Published
Abstract [en]

The 3D organisation of the genome in interphase cells is not a randomly folded polymer. Rather, experiments show that chromosomes arrange into a network of 3D compartments that correlate with biological processes, such as transcription, chromatin modifications and protein binding. However, these compartments do not exist during cell division when the DNA is condensed, and it is unclear how and when they emerge. In this paper, we focus on the early stages after cell division as the chromosomes start to decondense. We use a simple polymer model to understand the types of 3D structures that emerge from local unfolding of a compact initial state. From simulations, we recover 3D compartments, such as TADs and A/B compartments that are consistently detected in chromosome capture experiments across cell types and organisms. This suggests that the large-scale 3D organisation is a result of an inflation process.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Nuclear structure, Polymer simulation, Chromosome decondensation, Hi-C
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-157199 (URN)10.1007/s00412-018-0684-7 (DOI)000459275000003 ()30357462 (PubMedID)
Available from: 2019-04-08 Created: 2019-04-08 Last updated: 2019-09-05Bibliographically approved
Sobhy, H., Kumar, R., Lewerentz, J., Lizana, L. & Stenberg, P. (2019). Highly interacting regions of the human genome are enriched with enhancers and bound by DNA repair proteins. Scientific Reports, 9, Article ID 4577.
Open this publication in new window or tab >>Highly interacting regions of the human genome are enriched with enhancers and bound by DNA repair proteins
Show others...
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4577Article in journal (Refereed) Published
Abstract [en]

In specific cases, chromatin clearly forms long-range loops that place distant regulatory elements in close proximity to transcription start sites, but we have limited understanding of many loops identified by Chromosome Conformation Capture (such as Hi-C) analyses. In efforts to elucidate their characteristics and functions, we have identified highly interacting regions (HIRs) using intra-chromosomal Hi-C datasets with a new computational method based on looking at the eigenvector that corresponds to the smallest eigenvalue (here unity). Analysis of these regions using ENCODE data shows that they are in general enriched in bound factors involved in DNA damage repair and have actively transcribed genes. However, both highly transcribed regions as well as transcriptionally inactive regions can form HIRs. The results also indicate that enhancers and super-enhancers in particular form long-range interactions within the same chromosome. The accumulation of DNA repair factors in most identified HIRs suggests that protection from DNA damage in these regions is essential for avoidance of detrimental rearrangements.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-157750 (URN)10.1038/s41598-019-40770-9 (DOI)000461159600054 ()30872630 (PubMedID)2-s2.0-85063013118 (Scopus ID)
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-09Bibliographically approved
Pant, A., Kumar, R., Wani, N. A., Verma, S., Sharma, R., Pande, V., . . . Pandey, K. C. (2018). Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases. Scientific Reports, 8, Article ID 16193.
Open this publication in new window or tab >>Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases
Show others...
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16193Article in journal (Refereed) Published
Abstract [en]

Falcipains are major haemoglobinases of Plasmodium falciparum required for parasite growth and development. They consist of pro- and mature domains that interact via 'hot-spot' interactions and maintain the structural integrity of enzyme in zymogen state. Upon sensing the acidic environment, these interactions dissociate and active enzyme is released. For inhibiting falcipains, several active site inhibitors exist, however, compounds that target via allosteric mechanism remains uncharacterized. Therefore, we designed and synthesized six azapeptide compounds, among which, NA-01 & NA-03 arrested parasite growth by specifically blocking the auto-processing of falcipains. Inhibitors showed high affinity for enzymes in presence of the prodomain without affecting the secondary structure. Binding of NA-03 at the interface induced rigidity in the prodomain preventing structural reorganization. We further reported a histidine-dependent activation of falcipain. Collectively, for the first time we provide a framework for blocking the allosteric site of crucial haemoglobinases of the human malaria parasite. Targeting the allosteric site could provide high selectivity and less vulnerable to drug resistance.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153551 (URN)10.1038/s41598-018-34564-8 (DOI)000448950500045 ()30385827 (PubMedID)
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2018-11-22Bibliographically approved
Prasad, B., Jamroskovic, J., Bhowmik, S., Kumar, R., Romell, T., Sabouri, N. & Chorell, E. (2018). Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA. Chemistry - A European Journal, 24(31), 7926-7938
Open this publication in new window or tab >>Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
Show others...
2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 31, p. 7926-7938Article in journal (Refereed) Published
Abstract [en]

Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
DNA structures, G-quadruplexes, bis-indoles, drug design, nitrogen heterocycles
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-148052 (URN)10.1002/chem.201800078 (DOI)000434216600019 ()29603472 (PubMedID)2-s2.0-85048327004 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-11-01Bibliographically approved
Kumar, R., Sobhy, H., Stenberg, P. & Lizana, L. (2017). Genome contact map explorer: a platform for the comparison, interactive visualization and analysis of genome contact maps. Nucleic Acids Research, 45(17), Article ID e152.
Open this publication in new window or tab >>Genome contact map explorer: a platform for the comparison, interactive visualization and analysis of genome contact maps
2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 17, article id e152Article in journal (Refereed) Published
Abstract [en]

Hi-C experiments generate data in form of large genome contact maps (Hi-C maps). These show that chromosomes are arranged in a hierarchy of three-dimensional compartments. But to understand how these compartments form and by how much they affect genetic processes such as gene regulation, biologists and bioinformaticians need efficient tools to visualize and analyze Hi-C data. However, this is technically challenging because these maps are big. In this paper, we remedied this problem, partly by implementing an efficient file format and developed the genome contact map explorer platform. Apart from tools to process Hi-C data, such as normalization methods and a programmable interface, we made a graphical interface that let users browse, scroll and zoom Hi-C maps to visually search for patterns in the Hi-C data. In the software, it is also possible to browse several maps simultaneously and plot related genomic data. The software is openly accessible to the scientific community.

National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:umu:diva-141590 (URN)10.1093/nar/gkx644 (DOI)000412008000001 ()28973466 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2014–0018The Kempe Foundations, JCK-1347
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2018-06-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7268-9519

Search in DiVA

Show all publications