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Publications (9 of 9) Show all publications
Arnqvist, G., Westerberg, I., Galbraith, J., Sayadi, A., Scofield, D. G., Olsen, R.-A., . . . Suh, A. (2024). A chromosome-level assembly of the seed beetle Callosobruchus maculatus genome with annotation of its repetitive elements. G3: Genes, Genomes, Genetics, 14(2), Article ID jkad266.
Open this publication in new window or tab >>A chromosome-level assembly of the seed beetle Callosobruchus maculatus genome with annotation of its repetitive elements
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2024 (English)In: G3: Genes, Genomes, Genetics, E-ISSN 2160-1836, Vol. 14, no 2, article id jkad266Article in journal (Refereed) Published
Abstract [en]

Callosobruchus maculatus is a major agricultural pest of legume crops worldwide and an established model system in ecology and evolution. Yet, current molecular biological resources for this species are limited. Here, we employ Hi-C sequencing to generate a greatly improved genome assembly and we annotate its repetitive elements in a dedicated in-depth effort where we manually curate and classify the most abundant unclassified repeat subfamilies. We present a scaffolded chromosome-level assembly, which is 1.01 Gb in total length with 86% being contained within the 9 autosomes and the X chromosome. Repetitive sequences accounted for 70% of the total assembly. DNA transposons covered 18% of the genome, with the most abundant superfamily being Tc1-Mariner (9.75% of the genome). This new chromosome-level genome assembly of C. maculatus will enable future genetic and evolutionary studies not only of this important species but of beetles more generally. 

Keywords
Chrysomelidae, chromosome conformation capture, X chromosome assembly, transposable elements, Tc1-Mariner
National Category
Genetics
Identifiers
urn:nbn:se:su:diva-225411 (URN)10.1093/g3journal/jkad266 (DOI)001123598000001 ()38092066 (PubMedID)2-s2.0-85184664621 (Scopus ID)
Available from: 2024-01-16 Created: 2024-01-16 Last updated: 2024-02-21Bibliographically approved
Sekar, V., Mármol-Sánchez, E., Kalogeropoulos, P., Stanicek, L., Sagredo, E., Widmark, A., . . . Friedländer, M. R. (2024). Detection of transcriptome-wide microRNA-target interactions in single cells with agoTRIBE. Nature Biotechnology, 1296-1302
Open this publication in new window or tab >>Detection of transcriptome-wide microRNA-target interactions in single cells with agoTRIBE
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2024 (English)In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, p. 1296-1302Article in journal (Refereed) Published
Abstract [en]

MicroRNAs (miRNAs) exert their gene regulatory effects on numerous biological processes based on their selection of target transcripts. Current experimental methods available to identify miRNA targets are laborious and require millions of cells. Here we have overcome these limitations by fusing the miRNA effector protein Argonaute2 to the RNA editing domain of ADAR2, allowing the detection of miRNA targets transcriptome-wide in single cells. miRNAs guide the fusion protein to their natural target transcripts, causing them to undergo A>I editing, which can be detected by sensitive single-cell RNA sequencing. We show that agoTRIBE identifies functional miRNA targets, which are supported by evolutionary sequence conservation. In one application of the method we study microRNA interactions in single cells and identify substantial differential targeting across the cell cycle. AgoTRIBE also provides transcriptome-wide measurements of RNA abundance and allows the deconvolution of miRNA targeting in complex tissues at the single-cell level.

National Category
Bioinformatics and Systems Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-223224 (URN)10.1038/s41587-023-01951-0 (DOI)001071129200003 ()37735263 (PubMedID)2-s2.0-85171647219 (Scopus ID)
Available from: 2023-11-06 Created: 2023-11-06 Last updated: 2024-09-11Bibliographically approved
Llinàs-Arias, P., Ensenyat-Méndez, M., Orozco, J. I. J., Íñiguez-Muñoz, S., Valdez, B., Wang, C., . . . Marzese, D. M. (2023). 3-D chromatin conformation, accessibility, and gene expression profiling of triple-negative breast cancer. BMC Genomic Data, 24(1), Article ID 61.
Open this publication in new window or tab >>3-D chromatin conformation, accessibility, and gene expression profiling of triple-negative breast cancer
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2023 (English)In: BMC Genomic Data, ISSN 2730-6844, Vol. 24, no 1, article id 61Article in journal (Refereed) Published
Abstract [en]

Objectives Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Unlike other breast cancer subtypes, the scarcity of specific therapies and greater frequencies of distant metastases contribute to its aggressiveness. We aimed to find epigenetic changes that aid in the understanding of the dissemination process of these cancers.

Data description Using CRISPR/Cas9, our experimental approach led us to identify and disrupt an insulator element, IE8, whose activity seemed relevant for cell invasion. The experiments were performed in two well-established TNBC cellular models, the MDA-MB-231 and the MDA-MB-436. To gain insights into the underlying molecular mechanisms of TNBC invasion ability, we generated and characterized high-resolution chromatin interaction (Hi-C) and chromatin accessibility (ATAC-seq) maps in both cell models and complemented these datasets with gene expression profiling (RNA-seq) in MDA-MB-231, the cell line that showed more significant changes in chromatin accessibility. Altogether, our data provide a comprehensive resource for understanding the spatial organization of the genome in TNBC cells, which may contribute to accelerating the discovery of TNBC-specific alterations triggering advances for this devastating disease.

Keywords
Epigenetic profiling, Chromatin accessibility, Long-range interactions, RNA levels, ATAC-seq, Hi-C, RNA-seq, MDA-MB-436, MDA-MB-231
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-223863 (URN)10.1186/s12863-023-01166-x (DOI)001092189200001 ()37919672 (PubMedID)2-s2.0-85175719906 (Scopus ID)
Available from: 2023-11-22 Created: 2023-11-22 Last updated: 2023-11-22Bibliographically approved
Domingo-Prim, J., Bonath, F. & Visa, N. (2020). RNA at DNA Double-Strand Breaks: The Challenge of Dealing with DNA. Bioessays, 42(5), Article ID 1900225.
Open this publication in new window or tab >>RNA at DNA Double-Strand Breaks: The Challenge of Dealing with DNA
2020 (English)In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 42, no 5, article id 1900225Article, review/survey (Refereed) Published
Abstract [en]

RNA polymerase II is recruited to DNA double-strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage-induced long non-coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA-like molecules or degraded by different ribonucleases. They can also form double-stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute to the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR.

Keywords
DNA repair, EXOSC10, exosome, homologous recombination, RNA clearance, RNAse H, transcription
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-180366 (URN)10.1002/bies.201900225 (DOI)000516663600001 ()32105369 (PubMedID)
Available from: 2020-04-03 Created: 2020-04-03 Last updated: 2022-03-23Bibliographically approved
Domingo-Prim, J., Endara-Coll, M., Bonath, F., Jimeno, S., Prados-Carvaja, R., Friedländer, M. R., . . . Visa, N. (2019). EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks. Nature Communications, 10, Article ID 2135.
Open this publication in new window or tab >>EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
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2019 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 2135Article in journal (Refereed) Published
Abstract [en]

The exosome is a ribonucleolytic complex that plays important roles in RNA metabolism. Here we show that the exosome is necessary for the repair of DNA double-strand breaks (DSBs) in human cells and that RNA clearance is an essential step in homologous recombination. Transcription of DSB-flanking sequences results in the production of damage-induced long non-coding RNAs (dilncRNAs) that engage in DNA-RNA hybrid formation. Depletion of EXOSC10, an exosome catalytic subunit, leads to increased dilncRNA and DNA-RNA hybrid levels. Moreover, the targeting of the ssDNA-binding protein RPA to sites of DNA damage is impaired whereas DNA end resection is hyper-stimulated in EXOSC10-depleted cells. The DNA end resection deregulation is abolished by transcription inhibitors, and RNase H1 overexpression restores the RPA recruitment defect caused by EXOSC10 depletion, which suggests that RNA clearance of newly synthesized dilncRNAs is required for RPA recruitment, controlled DNA end resection and assembly of the homologous recombination machinery.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-169245 (URN)10.1038/s41467-019-10153-9 (DOI)000467703400003 ()31086179 (PubMedID)
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2023-03-28Bibliographically approved
Bonath, F., Domingo-Prim, J., Tarbier, M., Friedländer, M. R. & Visa, N. (2018). Next-generation sequencing reveals two populations of damage-induced small RNAs at endogenous DNA double-strand breaks. Nucleic Acids Research, 46(22), 11869-11882
Open this publication in new window or tab >>Next-generation sequencing reveals two populations of damage-induced small RNAs at endogenous DNA double-strand breaks
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 22, p. 11869-11882Article in journal (Refereed) Published
Abstract [en]

Recent studies suggest that transcription takes place at DNA double-strand breaks (DSBs), that transcripts at DSBs are processed by Drosha and Dicer into damage-induced small RNAs (diRNAs), and that diRNAs are required for DNA repair. However, diRNAs have been mostly detected in reporter constructs or repetitive sequences, and their existence at endogenous loci has been questioned by recent reports. Using the homing endonuclease I-PpoI, we have investigated diRNA production in genetically unperturbed human and mouse cells. I-PpoI is an ideal tool to clarify the requirements for diRNA production because it induces DSBs in different types of loci: the repetitive 28S locus, unique genes and intergenic loci. We show by extensive sequencing that the rDNA locus produces substantial levels of diRNAs, whereas unique genic and intergenic loci do not. Further characterization of diRNAs emerging from the 28S locus reveals the existence of two diRNA subtypes. Surprisingly, Drosha and its partner DGCR8 are dispensable for diRNA production and only one diRNAs subtype depends on Dicer processing. Furthermore, we provide evidence that diRNAs are incorporated into Argonaute. Our findings provide direct evidence for diRNA production at endogenous loci in mammalian cells and give insights into RNA processing at DSBs.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-166853 (URN)10.1093/nar/gky1107 (DOI)000456714000022 ()30418607 (PubMedID)
Available from: 2019-03-07 Created: 2019-03-07 Last updated: 2022-03-23Bibliographically approved
Domingo-Prim, J., Endara-Coll, M., Bonath, F., Jimeno, S., Friedländer, M., Huertas, P. & Visa, N.EXOSC10 is required for RPA assembly and controlled DNA resection at DNA dobule-strand breaks.
Open this publication in new window or tab >>EXOSC10 is required for RPA assembly and controlled DNA resection at DNA dobule-strand breaks
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-155687 (URN)
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2022-02-26Bibliographically approved
Tarbier, M., D. Mackowiak, S., Sekar, V., Bonath, F., Yapar, E., Fromm, B., . . . Friedländer, M. R.Landscape of microRNA and target expression variation and covariation in single mouse embryonic stem cells.
Open this publication in new window or tab >>Landscape of microRNA and target expression variation and covariation in single mouse embryonic stem cells
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

MicroRNAs are small RNA molecules that can repress the expression of protein coding genes post-transcriptionally. Previous studies have shown that microRNAs can also have alternative functions including target noise buffering and co-expression, but these observations have been limited to a few microRNAs. Here we systematically study microRNA alternative functions in mouse embryonic stem cells, by genetically deleting Drosha - leading to global loss of microRNAs. We apply complementary single-cell RNA-seq methods to study the variation of the targets and the microRNAs themselves, and transcriptional inhibition to measure target half-lives. We find that microRNAs form four distinct co-expression groups across single cells. In particular the mir-290 and the mir-182 clusters are abundantly, variably and inversely expressed. Intriguingly, some cells have global biases towards specific miRNAs originating from either end of the hairpin precursor, suggesting the presence of unknown regulatory cofactors. We find that miRNAs generally increase variation and covariation of their targets at the RNA level, but we also find miRNAs such as miR-182 that appear to have opposite functions. In particular, miRNAs that are themselves variable in expression, such as miR-291a, are more likely to induce covariations. In summary, we apply genetic perturbation and multi-omics to give the first global picture of microRNA dynamics at the single cell level. 

Keywords
miRNA, single-cells, biogenesis, gene expression noise, gene expression variation
National Category
Biological Sciences Bioinformatics and Systems Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-228941 (URN)10.1101/2024.03.24.586475 (DOI)
Funder
Swedish Research Council, Grant no. 2019-05320, ‘MioPec’Swedish Research Council, Consolidator Grant no. 2022-03953 ‘InSync’EU, European Research Council, Starting Grant no. 758397, ‘miRCell’
Available from: 2024-05-06 Created: 2024-05-06 Last updated: 2024-05-07
Bonath, F., Domingo-Prim, J., Tarbier, M., Friedländer, M. & Visa, N. Next-generation sequencing reveals two populations of damage- induced small RNAs at endogenous DNA double-strand breaks. Nucleic Acids Research
Open this publication in new window or tab >>Next-generation sequencing reveals two populations of damage- induced small RNAs at endogenous DNA double-strand breaks
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(English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962Article in journal (Refereed) Submitted
National Category
Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-155685 (URN)
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2022-02-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1270-1504

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