Mads Bengtsen

• Gundersen, Kristian; Bruusgaard, Jo C.; Egner, Ingrid Marie; Eftestøl, Einar & Bengtsen, Mads (2018). Muscle memory: virtues of your youth?. Journal of Physiology.  ISSN 0022-3751.  596(18), s 4289- 4290 . doi: 10.1113/JP276354
• Rodriguez- Castañeda, Fernando; Lemma, Roza Berhanu; Cuervo Torre, Ignacio; Bengtsen, Mads; Moen, Lisa Marie; Ledsaak, Marit; Eskeland, Ragnhild & Gabrielsen, Odd Stokke (2018). The SUMO protease SENP1 and the chromatin remodeller CHD3 interact and jointly affect chromatin accessibility and gene expression. Journal of Biological Chemistry.  ISSN 0021-9258.  293(40), s 15439- 15454 . doi: 10.1074/jbc.RA118.002844 Fulltekst i vitenarkiv. Vis sammendrag

  The small ubiquitin-like modifier (SUMO) post-translationally modifies lysine residues of transcription factors and co-regulators and thereby contributes to an important layer of control of the activities of these transcriptional regulators. Likewise, deSUMOylation of these factors by the sentrin-specific proteases (SENPs) also plays a role in gene regulation, but whether SENPs functionally interact with other regulatory factors that control gene expression is unclear. In the present work, we focused on SENP1, specifically, on its role in activation of gene expression investigated through analysis of the SENP1 interactome, which revealed that SENP1 physically interacts with the chromatin remodeler chromodomain helicase DNA-binding protein 3 (CHD3). Using several additional methods, including GST pull-down and co-immunoprecipitation assays, we validated and mapped this interaction, and using CRISPR-Cas9–generated CHD3- and SENP1-KO cells (in the haploid HAP1 cell line), we investigated whether these two proteins are functionally linked in regulating chromatin remodeling and gene expression. Genome-wide ATAC-Seq analysis of the CHD3- and SENP1-KO cells revealed a large degree of overlap in differential chromatin openness between these two mutant cell lines. Moreover, motif analysis and comparison with ChIP-Seq profiles in K562 cells pointed to an association of CHD3 and SENP1 with CCCTC-binding factor (CTCF) and SUMOylated chromatin–associated factors. Lastly, genome-wide RNA-Seq also indicated that these two proteins co-regulate the expression of several genes. We propose that the functional link between chromatin remodeling by CHD3 and deSUMOylation by SENP1 uncovered here provides another level of control of gene expression.

• Winje, Ivan; Bengtsen, Mads; Eftestøl, Einar; Juvkam, Inga; Bruusgaard, Jo C. & Gundersen, Kristian (2018). Specific labelling of myonuclei by an antibody against pericentriolar material 1 on skeletal muscle tissue sections. Acta Physiologica.  ISSN 1748-1708.  223(4), s 1- 9 . doi: 10.1111/apha.13034 Fulltekst i vitenarkiv.
• Bengtsen, Mads; Sørensen, Linda Therese; Aabel, Linn Ingeborg; Ledsaak, Marit; Matre, Vilborg & Gabrielsen, Odd Stokke (2017). The adaptor protein ARA55 and the nuclear kinase HIPK1 assist c-Myb in recruiting p300 to chromatin. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms.  ISSN 1874-9399.  1860(7), s 751- 760 . doi: 10.1016/j.bbagrm.2017.05.001 Fulltekst i vitenarkiv.
• Simovski, Boris; Vodak, Daniel; Gundersen, Sveinung; Domanska, Diana Ewa; Azab, Abdulrahman; Holden, Lars; Holden, Marit; Grytten, Ivar; Rand, Knut Dagestad; Drabløs, Finn; Johansen, Morten; Mora Ortiz, Antonio Carlos; Lund-Andersen, Christin; Fromm, Bastian; Eskeland, Ragnhild; Gabrielsen, Odd Stokke; Ferkingstad, Egil; Nakken, Sigve; Bengtsen, Mads; Nederbragt, Alexander Johan; Thorarensen, Hildur Sif; Akse, Johannes Andreas; Glad, Ingrid Kristine; Hovig, Johannes Eivind & Sandve, Geir Kjetil (2017). GSuite HyperBrowser: integrative analysis of dataset collections across the genome and epigenome. GigaScience.  ISSN 2047-217X.  6(7), s 1- 12 . doi: 10.1093/gigascience/gix032 Fulltekst i vitenarkiv. Vis sammendrag

  Background: Recent large-scale undertakings such as ENCODE and Roadmap Epigenomics have generated experimental data mapped to the human reference genome (as genomic tracks) representing a variety of functional elements across a large number of cell types. Despite the high potential value of these publicly available data for a broad variety of investigations, little attention has been given to the analytical methodology necessary for their widespread utilisation. Findings: We here present a first principled treatment of the analysis of collections of genomic tracks. We have developed novel computational and statistical methodology to permit comparative and confirmatory analyses across multiple and disparate data sources. We delineate a set of generic questions that are useful across a broad range of investigations and discuss the implications of choosing different statistical measures and null models. Examples include contrasting analyses across different tissues or diseases. The methodology has been implemented in a comprehensive open-source software system, the GSuite HyperBrowser. To make the functionality accessible to biologists, and to facilitate reproducible analysis, we have also developed a web-based interface providing an expertly guided and customizable way of utilizing the methodology. With this system, many novel biological questions can flexibly be posed and rapidly answered. Conclusions: Through a combination of streamlined data acquisition, interoperable representation of dataset collections and customizable statistical analysis with guided setup and interpretation, the GSuite HyperBrowser represents a first comprehensive solution for integrative analysis of track collections across the genome and epigenome. The software is available at: https://hyperbrowser.uio.no

• Ledsaak, Marit; Bengtsen, Mads; Molværsmyr, Ann-Kristin; Fuglerud, Bettina Maria; Matre, Vilborg; Eskeland, Ragnhild & Gabrielsen, Odd Stokke (2016). PIAS1 binds p300 and behaves as a coactivator or corepressor of the transcription factor c-Myb dependent on SUMO-status. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms.  ISSN 1874-9399.  1859(5), s 705- 718 . doi: 10.1016/j.bbagrm.2016.03.011
• Bengtsen, Mads; Klepper, Kjetil; Gundersen, Sveinung; Cuervo Torre, Ignacio; Drabløs, Finn; Hovig, Johannes Eivind; Sandve, Geir Kjetil F.; Gabrielsen, Odd Stokke & Eskeland, Ragnhild (2015). c-Myb Binding Sites in Haematopoietic Chromatin Landscapes. PLOS ONE.  ISSN 1932-6203.  10(7) . doi: 10.1371/journal.pone.0133280 Fulltekst i vitenarkiv. Vis sammendrag

  Strict control of tissue-specific gene expression plays a pivotal role during lineage commit- ment. The transcription factor c-Myb has an essential role in adult haematopoiesis and func- tions as an oncogene when rearranged in human cancers. Here we have exploited digital genomic footprinting analysis to obtain a global picture of c-Myb occupancy in the genome of six different haematopoietic cell-types. We have biologically validated several c-Myb foot- prints using c-Myb knockdown data, reporter assays and DamID analysis. We show that our predicted conserved c-Myb footprints are highly dependent on the haematopoietic cell type, but that there is a group of gene targets common to all cell-types analysed. Further- more, we find that c-Myb footprints co-localise with active histone mark H3K4me3 and are significantly enriched at exons. We analysed co-localisation of c-Myb footprints with 104 chromatin regulatory factors in K562 cells, and identified nine proteins that are enriched together with c-Myb footprints on genes positively regulated by c-Myb and one protein enriched on negatively regulated genes. Our data suggest that c-Myb is a transcription fac- tor with multifaceted target regulation depending on cell type.

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• Bengtsen, Mads (2017). A model for studying epigenetics in muscles.
• Bengtsen, Mads (2016). The Transcription Factor c-Myb - Investigation of its Genome-wide Occupancy and Activation Mechanisms. Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo.. 1741.
• Sæther, Thomas; Bengtsen, Mads; Molværsmyr, Ann-Kristin; Pattabiraman, D.R.; Alm-Kristiansen, Anne Hege; Ledsaak, Marit; Gonda, T.J. & Gabrielsen, Odd Stokke (2012). Regulating the regulator: SUMO functions as a master switch for the transcription factor c-Myb. Vis sammendrag

  The oncoprotein c-Myb is an essential hematopoietic transcription factor that controls proliferation and differentiation of progenitors during blood cell development. This transcriptional activator plays a direct role in lineage fate selection, cell cycle progression, and differentiation of myeloid as well as B- and T-lymphoid progenitors. Recent studies have shown that c-Myb accomplishes this by controlling the expression of several important hematopoietic transcriptions factors, and in that way acts as a master regulator. c-Myb is modified by SUMO on two lysines in its C-terminal regulatory domain (CRD), and is able to bind SUMO via a SUMO-interacting motif (SIM) in the central transactivation domain. Both these SUMO-contacts are important in regulating the transactivation activity of c-Myb, and breaking these contacts makes c-Myb super active. We have found that the ability of c-Myb to synergize with other transcription factors on compound promoters is restricted by synergy control, linked to the SUMOylation of CRD. De-SUMOylation of c-Myb leads to a dramatic change in synergy behavior, which correlates with a SUMO-dependent differential recruitment of p300 and a corresponding local change in histone H3 and H4 acetylation. Using cell-based transformation assays, we have addressed the abilities of c-Myb SUMO binding and conjugation mutants to transform hematopoietic cells. Interestingly, only loss of SUMO binding, and not SUMO conjugation, enhances the myeloid transformational potential of c-Myb. c-Myb with the SIM mutated confers a high proliferative ability and causes an effective differentiation block. This establishes SUMO binding as a mechanism responsible for keeping the transforming potential of the oncoprotein in check. Taken together this implies that SUMO functions as a master regulatory switch for c-Myb. Given that the SUMO-system may be perturbed in different cancers, c-Myb may be particularly vulnerable to such changes and thus mediate dramatic downstream effects.

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