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Remeseiro, Silvia
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Publikasjoner (10 av 10) Visa alla publikasjoner
Dennhag, N., Kahsay, A., Nissen, I., Nord, H., Chermenina, M., Liu, J., . . . Domellöf, F. P. (2024). fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles. Nature Communications, 15(1), Article ID 1950.
Åpne denne publikasjonen i ny fane eller vindu >>fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
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2024 (engelsk)Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikkel-id 1950Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.

sted, utgiver, år, opplag, sider
Springer Nature, 2024
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-222359 (URN)10.1038/s41467-024-46187-x (DOI)38431640 (PubMedID)2-s2.0-85186557555 (Scopus ID)
Tilgjengelig fra: 2024-03-15 Laget: 2024-03-15 Sist oppdatert: 2024-03-15bibliografisk kontrollert
López-Pérez, A. R., Remeseiro, S. & Hörnblad, A. (2023). Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice. Scientific Reports, 13(1), Article ID 18666.
Åpne denne publikasjonen i ny fane eller vindu >>Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice
2023 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 13, nr 1, artikkel-id 18666Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Several preclinical models have been recently developed for metabolic associated fatty liver disease (MAFLD) and associated hepatocellular carcinoma (HCC) but comprehensive analysis of the regulatory and transcriptional landscapes underlying disease in these models are still missing. We investigated the regulatory and transcriptional landscape in fatty livers and liver tumours from DIAMOND mice that faithfully mimic human HCC development in the context of MAFLD. RNA-sequencing and ChIP-sequencing revealed rewiring of the Wnt/β-catenin regulatory network in DIAMOND tumours, as manifested by chromatin remodelling and associated switching in the expression of the canonical TCF/LEF downstream effectors. We identified splicing as a major mechanism leading to constitutive oncogenic activation of β-catenin in a large subset of DIAMOND tumours, a mechanism that is independent on somatic mutations in the locus and that has not been previously shown. Similar splicing events were found in a fraction of human HCC and hepatoblastoma samples.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2023
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-216658 (URN)10.1038/s41598-023-45614-1 (DOI)37907668 (PubMedID)2-s2.0-85175645830 (Scopus ID)
Forskningsfinansiär
The Kempe Foundations, SMK-1863The Kempe Foundations, JCK-2149Cancerforskningsfonden i Norrland, AMP 18-940Cancerforskningsfonden i Norrland, AMP 21-1043Lions Cancerforskningsfond i Norr, LP 20-2232Lions Cancerforskningsfond i Norr, LP 22-2313
Tilgjengelig fra: 2023-11-28 Laget: 2023-11-28 Sist oppdatert: 2023-11-28bibliografisk kontrollert
Vincent, C. A., Nissen, I., Dakhel, S., Hörnblad, A. & Remeseiro, S. (2023). Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide. BMC Cancer, 23(1), Article ID 945.
Åpne denne publikasjonen i ny fane eller vindu >>Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide
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2023 (engelsk)Inngår i: BMC Cancer, E-ISSN 1471-2407, Vol. 23, nr 1, artikkel-id 945Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Glioblastoma (GB) is the most aggressive of all primary brain tumours and due to its highly invasive nature, surgical resection is nearly impossible. Patients typically rely on radiotherapy with concurrent temozolomide (TMZ) treatment and face a median survival of ~ 14 months. Alterations in the Epidermal Growth Factor Receptor gene (EGFR) are common in GB tumours, but therapies targeting EGFR have not shown significant clinical efficacy.

Methods: Here, we investigated the influence of the EGFR regulatory genome on GB cells and identified novel EGFR enhancers located near the GB-associated SNP rs723527. We used CRISPR/Cas9-based approaches to target the EGFR enhancer regions, generating multiple modified GB cell lines, which enabled us to study the functional response to enhancer perturbation.

Results: Epigenomic perturbation of the EGFR regulatory region decreases EGFR expression and reduces the proliferative and invasive capacity of glioblastoma cells, which also undergo a metabolic reprogramming in favour of mitochondrial respiration and present increased apoptosis. Moreover, EGFR enhancer-perturbation increases the sensitivity of GB cells to TMZ, the first-choice chemotherapeutic agent to treat glioblastoma.

Conclusions: Our findings demonstrate how epigenomic perturbation of EGFR enhancers can ameliorate the aggressiveness of glioblastoma cells and enhance the efficacy of TMZ treatment. This study demonstrates how CRISPR/Cas9-based perturbation of enhancers can be used to modulate the expression of key cancer genes, which can help improve the effectiveness of existing cancer treatments and potentially the prognosis of difficult-to-treat cancers such as glioblastoma.

sted, utgiver, år, opplag, sider
BioMed Central (BMC), 2023
Emneord
CRISPR/Cas9, EGFR, Enhancer, Epigenomic perturbation, Glioblastoma
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-215716 (URN)10.1186/s12885-023-11418-9 (DOI)001082654500001 ()37803333 (PubMedID)2-s2.0-85173760974 (Scopus ID)
Forskningsfinansiär
Umeå UniversitySwedish Research Council, 2019–01960Swedish Cancer Society, 21 1720Knut and Alice Wallenberg FoundationThe Kempe Foundations, SMK-1964.2
Tilgjengelig fra: 2023-11-10 Laget: 2023-11-10 Sist oppdatert: 2024-07-04bibliografisk kontrollert
Chakraborty, C., Nissen, I., Vincent, C. A., Hägglund, A.-C., Hörnblad, A. & Remeseiro, S. (2023). Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication. Nature Communications, 14(1), Article ID 6446.
Åpne denne publikasjonen i ny fane eller vindu >>Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
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2023 (engelsk)Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikkel-id 6446Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer. Here, we map the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks in glioblastoma. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodelling. SMAD3 and PITX1 emerge as major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote proliferation of glioblastoma cells in co-culture with glutamatergic neurons, and in mice bearing patient-derived xenografts. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.

sted, utgiver, år, opplag, sider
Springer Nature, 2023
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-216189 (URN)10.1038/s41467-023-41919-x (DOI)37833281 (PubMedID)2-s2.0-85174178290 (Scopus ID)
Tilgjengelig fra: 2023-11-09 Laget: 2023-11-09 Sist oppdatert: 2023-11-09bibliografisk kontrollert
Hörnblad, A. & Remeseiro, S. (2022). Epigenetics, Enhancer Function and 3D Chromatin Organization in Reprogramming to Pluripotency. Cells, 11(9), Article ID 1404.
Åpne denne publikasjonen i ny fane eller vindu >>Epigenetics, Enhancer Function and 3D Chromatin Organization in Reprogramming to Pluripotency
2022 (engelsk)Inngår i: Cells, E-ISSN 2073-4409, Vol. 11, nr 9, artikkel-id 1404Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Genome architecture, epigenetics and enhancer function control the fate and identity of cells. Reprogramming to induced pluripotent stem cells (iPSCs) changes the transcriptional profile and chromatin landscape of the starting somatic cell to that of the pluripotent cell in a stepwise manner. Changes in the regulatory networks are tightly regulated during normal embryonic development to determine cell fate, and similarly need to function in cell fate control during reprogramming. Switching off the somatic program and turning on the pluripotent program involves a dynamic reorganization of the epigenetic landscape, enhancer function, chromatin accessibility and 3D chromatin topology. Within this context, we will review here the current knowledge on the processes that control the establishment and maintenance of pluripotency during somatic cell reprogramming.

sted, utgiver, år, opplag, sider
MDPI, 2022
Emneord
3D genome, enhancer, epigenetics, iPSCs, OSKM, pluripotency, reprogramming
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-194438 (URN)10.3390/cells11091404 (DOI)000794383200001 ()2-s2.0-85128512329 (Scopus ID)
Tilgjengelig fra: 2022-05-05 Laget: 2022-05-05 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Dakhel, S., Davies, W. I. L., Joseph, J. V., Tomar, T., Remeseiro, S. & Gunhaga, L. (2021). Chick fetal organ spheroids as a model to study development and disease. BMC Molecular and Cell Biology, 22(1), Article ID 37.
Åpne denne publikasjonen i ny fane eller vindu >>Chick fetal organ spheroids as a model to study development and disease
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2021 (engelsk)Inngår i: BMC Molecular and Cell Biology, E-ISSN 2661-8850, Vol. 22, nr 1, artikkel-id 37Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND: Organ culture models have been used over the past few decades to study development and disease. The in vitro three-dimensional (3D) culture system of organoids is well known, however, these 3D systems are both costly and difficult to culture and maintain. As such, less expensive, faster and less complex methods to maintain 3D cell culture models would complement the use of organoids. Chick embryos have been used as a model to study human biology for centuries, with many fundamental discoveries as a result. These include cell type induction, cell competence, plasticity and contact inhibition, which indicates the relevance of using chick embryos when studying developmental biology and disease mechanisms.

RESULTS: Here, we present an updated protocol that enables time efficient, cost effective and long-term expansion of fetal organ spheroids (FOSs) from chick embryos. Utilizing this protocol, we generated FOSs in an anchorage-independent growth pattern from seven different organs, including brain, lung, heart, liver, stomach, intestine and epidermis. These three-dimensional (3D) structures recapitulate many cellular and structural aspects of their in vivo counterpart organs and serve as a useful developmental model. In addition, we show a functional application of FOSs to analyze cell-cell interaction and cell invasion patterns as observed in cancer.

CONCLUSION: The establishment of a broad ranging and highly effective method to generate FOSs from different organs was successful in terms of the formation of healthy, proliferating 3D organ spheroids that exhibited organ-like characteristics. Potential applications of chick FOSs are their use in studies of cell-to-cell contact, cell fusion and tumor invasion under defined conditions. Future studies will reveal whether chick FOSs also can be applicable in scientific areas such as viral infections, drug screening, cancer diagnostics and/or tissue engineering.

sted, utgiver, år, opplag, sider
BioMed Central (BMC), 2021
Emneord
3D cell culture, Cancer, Chick, Development, Fetal organ spheroids, Invasion
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-186439 (URN)10.1186/s12860-021-00374-6 (DOI)000669871300001 ()34225662 (PubMedID)2-s2.0-85110859058 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society, 18 0463Cancerforskningsfonden i Norrland
Tilgjengelig fra: 2021-08-02 Laget: 2021-08-02 Sist oppdatert: 2023-10-05bibliografisk kontrollert
López-Pérez, A. R., Norlin, S., Steneberg, P., Remeseiro, S., Edlund, H. & Hörnblad, A. (2021). Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice. Scientific Reports, 11(1), Article ID 24410.
Åpne denne publikasjonen i ny fane eller vindu >>Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice
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2021 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikkel-id 24410Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2021
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-190971 (URN)10.1038/s41598-021-03567-3 (DOI)000734163400004 ()34949756 (PubMedID)2-s2.0-85121738771 (Scopus ID)
Forskningsfinansiär
Knut and Alice Wallenberg Foundation, 2015.0278Swedish Research Council, 2018-05973The Kempe Foundations, SMK-1863
Tilgjengelig fra: 2022-01-04 Laget: 2022-01-04 Sist oppdatert: 2024-07-02bibliografisk kontrollert
Bahr, C., von Paleske, L., Uslu, V. V., Remeseiro, S., Takayama, N., Ng, S. W., . . . Spitz, F. (2018). A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies [Letter to the editor]. Nature, 553(7689), 515-520
Åpne denne publikasjonen i ny fane eller vindu >>A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
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2018 (engelsk)Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 553, nr 7689, s. 515-520Artikkel i tidsskrift, Letter (Fagfellevurdert) Published
Abstract [en]

The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies1. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a ‘super-enhancer’2 is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells3. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a ‘blood enhancer cluster’ (BENC). We show that BENC is also essential for the maintenance of MLL–AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-171861 (URN)10.1038/nature25193 (DOI)29342133 (PubMedID)
Tilgjengelig fra: 2020-06-18 Laget: 2020-06-18 Sist oppdatert: 2020-06-18bibliografisk kontrollert
Remeseiro, S., Hörnblad, A. & Spitz, F. (2016). Gene regulation during development in the light of topologically associating domains. Wiley Interdisciplinary Reviews: Developmental Biology, 5(2), 169-185
Åpne denne publikasjonen i ny fane eller vindu >>Gene regulation during development in the light of topologically associating domains
2016 (engelsk)Inngår i: Wiley Interdisciplinary Reviews: Developmental Biology, ISSN 1759-7684, E-ISSN 1759-7692, Vol. 5, nr 2, s. 169-185Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

During embryonic development, complex transcriptional programs govern the precision of gene expression. Many key developmental genes are regulated via cis-regulatory elements that are located far away in the linear genome. How sequences located hundreds of kilobases away from a promoter can influence its activity has been the subject of numerous speculations, which all underline the importance of the 3D-organization of the genome. The recent advent of chromosome conformation capture techniques has put into focus the subdivision of the genome into topologically associating domains (TADs). TADs may influence regulatory activities on multiple levels. The relative invariance of TAD limits across cell types suggests that they may form fixed structural domains that could facilitate and/or confine long-range regulatory interactions. However, most recent studies suggest that interactions within TADs are more variable and dynamic than initially described. Hence, different models are emerging regarding how TADs shape the complex 3D conformations, and thereafter influence the networks of cis-interactions that govern gene expression during development. For further resources related to this article, please visit the WIREs website.

HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-182707 (URN)10.1002/wdev.218 (DOI)26558551 (PubMedID)
Tilgjengelig fra: 2021-05-03 Laget: 2021-05-03 Sist oppdatert: 2021-05-03bibliografisk kontrollert
Dennhag, N., Kahsay, A., Nissen, I., Chermenina, M., Nord, H., Liu, J., . . . Domellöf, F. P. fhl2b expression ameliorates muscular dystrophy.
Åpne denne publikasjonen i ny fane eller vindu >>fhl2b expression ameliorates muscular dystrophy
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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-218164 (URN)
Tilgjengelig fra: 2023-12-18 Laget: 2023-12-18 Sist oppdatert: 2023-12-18
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