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Publications (10 of 18) Show all publications
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.
Open this publication in new window or tab >>Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice
2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 18666Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2023
National Category
Cell and Molecular Biology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-216658 (URN)10.1038/s41598-023-45614-1 (DOI)37907668 (PubMedID)2-s2.0-85175645830 (Scopus ID)
Funder
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
Available from: 2023-11-28 Created: 2023-11-28 Last updated: 2023-11-28Bibliographically approved
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.
Open this publication in new window or tab >>Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide
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2023 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 23, no 1, article id 945Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
CRISPR/Cas9, EGFR, Enhancer, Epigenomic perturbation, Glioblastoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215716 (URN)10.1186/s12885-023-11418-9 (DOI)001082654500001 ()37803333 (PubMedID)2-s2.0-85173760974 (Scopus ID)
Funder
Umeå UniversitySwedish Research Council, 2019–01960Swedish Cancer Society, 21 1720Knut and Alice Wallenberg FoundationThe Kempe Foundations, SMK-1964.2
Available from: 2023-11-10 Created: 2023-11-10 Last updated: 2023-11-10Bibliographically approved
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.
Open this publication in new window or tab >>Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 6446Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-216189 (URN)10.1038/s41467-023-41919-x (DOI)37833281 (PubMedID)2-s2.0-85174178290 (Scopus ID)
Available from: 2023-11-09 Created: 2023-11-09 Last updated: 2023-11-09Bibliographically approved
Hörnblad, A. & Remeseiro, S. (2022). Epigenetics, Enhancer Function and 3D Chromatin Organization in Reprogramming to Pluripotency. Cells, 11(9), Article ID 1404.
Open this publication in new window or tab >>Epigenetics, Enhancer Function and 3D Chromatin Organization in Reprogramming to Pluripotency
2022 (English)In: Cells, E-ISSN 2073-4409, Vol. 11, no 9, article id 1404Article, review/survey (Refereed) 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.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
3D genome, enhancer, epigenetics, iPSCs, OSKM, pluripotency, reprogramming
National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-194438 (URN)10.3390/cells11091404 (DOI)000794383200001 ()2-s2.0-85128512329 (Scopus ID)
Available from: 2022-05-05 Created: 2022-05-05 Last updated: 2023-09-05Bibliographically approved
Kahsay, A., Rodriguez-Marquez, E., López-Pérez, A. R., Hörnblad, A. & von Hofsten, J. (2022). Pax3 loss of function delays tumour progression in kRAS-induced zebrafish rhabdomyosarcoma models. Scientific Reports, 12(1), Article ID 17149.
Open this publication in new window or tab >>Pax3 loss of function delays tumour progression in kRAS-induced zebrafish rhabdomyosarcoma models
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 17149Article in journal (Refereed) Published
Abstract [en]

Rhabdomyosarcoma is a soft tissue cancer that arises in skeletal muscle due to mutations in myogenic progenitors that lead to ineffective differentiation and malignant transformation. The transcription factors Pax3 and Pax7 and their downstream target genes are tightly linked with the fusion positive alveolar subtype, whereas the RAS pathway is usually involved in the embryonal, fusion negative variant. Here, we analyse the role of Pax3 in a fusion negative context, by linking alterations in gene expression in pax3a/pax3b double mutant zebrafish with tumour progression in kRAS-induced rhabdomyosarcoma tumours. Several genes in the RAS/MAPK signalling pathway were significantly down-regulated in pax3a/pax3b double mutant zebrafish. Progression of rhabdomyosarcoma tumours was also delayed in the pax3a/pax3b double mutant zebrafish indicating that Pax3 transcription factors have an unappreciated role in mediating malignancy in fusion negative rhabdomyosarcoma.

Place, publisher, year, edition, pages
Nature Publishing Group, 2022
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-203323 (URN)10.1038/s41598-022-21525-5 (DOI)000867889200055 ()36229514 (PubMedID)2-s2.0-85139945677 (Scopus ID)
Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2023-01-18Bibliographically approved
Hörnblad, A., Bastide, S., Langenfeld, K., Langa, F. & Spitz, F. (2021). Dissection of the Fgf8 regulatory landscape by in vivo CRISPR-editing reveals extensive intra- and inter-enhancer redundancy. Nature Communications, 12(1), Article ID 439.
Open this publication in new window or tab >>Dissection of the Fgf8 regulatory landscape by in vivo CRISPR-editing reveals extensive intra- and inter-enhancer redundancy
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2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 439Article in journal (Refereed) Published
Abstract [en]

Developmental genes are often regulated by multiple elements with overlapping activity. Yet, in most cases, the relative function of those elements and their contribution to endogenous gene expression remain poorly characterized. An example of this phenomenon is that distinct sets of enhancers have been proposed to direct Fgf8 in the limb apical ectodermal ridge and the midbrain-hindbrain boundary. Using in vivo CRISPR/Cas9 genome engineering, we functionally dissect this complex regulatory ensemble and demonstrate two distinct regulatory logics. In the apical ectodermal ridge, the control of Fgf8 expression appears distributed between different enhancers. In contrast, we find that in the midbrain-hindbrain boundary, one of the three active enhancers is essential while the other two are dispensable. We further dissect the essential midbrain-hindbrain boundary enhancer to reveal that it is also composed by a mixture of essential and dispensable modules. Cross-species transgenic analysis of this enhancer suggests that its composition may have changed in the vertebrate lineage.

Place, publisher, year, edition, pages
Springer Nature, 2021
National Category
Developmental Biology
Identifiers
urn:nbn:se:umu:diva-180806 (URN)10.1038/s41467-020-20714-y (DOI)000613518600007 ()33469032 (PubMedID)2-s2.0-85099540540 (Scopus ID)
Available from: 2021-03-03 Created: 2021-03-03 Last updated: 2023-03-28Bibliographically approved
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.
Open this publication in new window or tab >>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 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 24410Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-190971 (URN)10.1038/s41598-021-03567-3 (DOI)000734163400004 ()34949756 (PubMedID)2-s2.0-85121738771 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2015.0278Swedish Research Council, 2018-05973The Kempe Foundations, SMK-1863
Available from: 2022-01-04 Created: 2022-01-04 Last updated: 2022-09-15Bibliographically approved
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
Open this publication in new window or tab >>Gene regulation during development in the light of topologically associating domains
2016 (English)In: Wiley Interdisciplinary Reviews: Developmental Biology, ISSN 1759-7684, E-ISSN 1759-7692, Vol. 5, no 2, p. 169-185Article in journal (Refereed) 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.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-182707 (URN)10.1002/wdev.218 (DOI)26558551 (PubMedID)
Available from: 2021-05-03 Created: 2021-05-03 Last updated: 2021-05-03Bibliographically approved
Hörnblad, A., Nord, C., Parween, S., Ahnfelt-Rønne, J. & Ahlgren, U. (2015). The pancreas (1ed.). In: Richard Baldock, Jonathan Bard, Duncan R. Davidson and Gillian Morriss-Kay (Ed.), Kaufman's atlas of mouse development supplement: with coronal sections (pp. 85-94). Elsevier
Open this publication in new window or tab >>The pancreas
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2015 (English)In: Kaufman's atlas of mouse development supplement: with coronal sections / [ed] Richard Baldock, Jonathan Bard, Duncan R. Davidson and Gillian Morriss-Kay, Elsevier, 2015, 1, p. 85-94Chapter in book (Refereed)
Abstract [en]

This chapter aims to provide a three-dimensional description of the key morphological events, through which a discrete region of the early gut epithelium, as well as its associated mesenchyme, gives rise to the adult pancreas. Facilitated by recent advances in optical imaging techniques, including light sheet fluorescence microscopy and optical projection tomography, we present image series illustrating the growth of the organ and the formation of key morphological and anatomical features. Given the close developmental relationship between the pancreas-associated mesenchyme and the spleen anlage, and thus the potential for the developing spleen to influence pancreas morphogenesis, we include a brief section which covers the early development of this organ. Finally, we describe the spatial and quantitative distribution of the pancreatic endocrine (β-cell) component in adult mice and highlight lobular heterogeneities that may affect phenotypical evaluations of the gland.

Place, publisher, year, edition, pages
Elsevier, 2015 Edition: 1
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-134657 (URN)10.1016/B978-0-12-800043-4.00006-3 (DOI)2-s2.0-85171007672 (Scopus ID)978-0-12-800043-4 (ISBN)978-0-12-800913-0 (ISBN)
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2023-10-12Bibliographically approved
Cheddad, A., Nord, C., Hörnblad, A., Prunskaite-Hyyryläinen, R., Eriksson, M., Georgsson, F., . . . Ahlgren, U. (2013). Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion. Optics Express, 21(14), 16584-16604
Open this publication in new window or tab >>Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion
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2013 (English)In: Optics Express, E-ISSN 1094-4087, Vol. 21, no 14, p. 16584-16604Article in journal (Refereed) Published
Abstract [en]

We demonstrate a technique to improve structural data obtained from Optical Projection Tomography (OPT) using Image Fusion (IF) and contrast normalization. This enables the visualization of molecular expression patterns in biological specimens with highly variable contrast values. In the approach, termed IF-OPT, different exposures are fused by assigning weighted contrasts to each. When applied to projection images from mouse organs and digital phantoms our results demonstrate the capability of IF-OPT to reveal high and low signal intensity details in challenging specimens. We further provide measurements to highlight the benefits of the new algorithm in comparison to other similar methods.

Place, publisher, year, edition, pages
Optical Society of America, 2013
National Category
Other Medical Biotechnology
Identifiers
urn:nbn:se:umu:diva-80512 (URN)10.1364/OE.21.016584 (DOI)000321819400038 ()23938510 (PubMedID)2-s2.0-84880537960 (Scopus ID)
Funder
Swedish Research CouncilEU, European Research Council, CP-IP 228933-2
Available from: 2013-09-19 Created: 2013-09-19 Last updated: 2023-03-23Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-1283-0784

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