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Sahlén, Pelin
Publications (5 of 5) Show all publications
Cavalli, M., Baltzer, N., Umer, H. M., Grau, J., Lemnian, I., Pan, G., . . . Wadelius, C. (2019). Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases. Scientific Reports, 9, Article ID 2695.
Open this publication in new window or tab >>Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2695Article in journal (Refereed) Published
Abstract [en]

Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Genetics
Identifiers
urn:nbn:se:kth:diva-246259 (URN)10.1038/s41598-019-39633-0 (DOI)000459571100059 ()30804403 (PubMedID)2-s2.0-85062099213 (Scopus ID)
Note

QC 20190327

Available from: 2019-03-27 Created: 2019-03-27 Last updated: 2019-03-27Bibliographically approved
Cavalli, M., Baltzer, N., Umer, H. M., Grau, J., Lemnian, I., Pan, G., . . . Wadelius, C. (2019). Allele specific chromatin signals, 3D interactions, and refined motif predictions for immune and B cell related diseases. Paper presented at 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), JUN 16-19, 2018, Milan, ITALY. European Journal of Human Genetics, 27, 611-611
Open this publication in new window or tab >>Allele specific chromatin signals, 3D interactions, and refined motif predictions for immune and B cell related diseases
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 611-611Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:kth:diva-262996 (URN)10.1038/s41431-019-0404-7 (DOI)000489313104367 ()2-s2.0-85069268023 (Scopus ID)
Conference
51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), JUN 16-19, 2018, Milan, ITALY
Note

QC 20191031

Available from: 2019-10-31 Created: 2019-10-31 Last updated: 2019-10-31Bibliographically approved
Åkerborg, Ö., Spalinskas, R., Pradhananga, S., Anil, A., Höjer, P., Poujade, F.-A., . . . Eriksson, P. (2019). High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways. Circulation. Genomic and precision medicine, 12(3), Article ID e002353.
Open this publication in new window or tab >>High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways
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2019 (English)In: Circulation. Genomic and precision medicine, ISSN 2574-8300, Vol. 12, no 3, article id e002353Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease. METHODS: In this study, we generated high-resolution genomic interaction maps (similar to 750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac. RESULTS: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. CONCLUSIONS: In summary, we present a catalog of candidate genes regulated by coronary artery disease-related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

Place, publisher, year, edition, pages
NLM (Medline), 2019
Keywords
coronary artery disease, gene, haplotype, inflammation, genomics
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:kth:diva-251721 (URN)10.1161/CIRCGEN.118.002353 (DOI)000466741300003 ()30786239 (PubMedID)2-s2.0-85063933618 (Scopus ID)
Note

QC 20190520

Available from: 2019-05-20 Created: 2019-05-20 Last updated: 2019-05-29Bibliographically approved
Zhang, W., Chronis, C., Chen, X., Zhang, H., Spalinskas, R., Pardo, M., . . . Plath, K. (2019). The BAF and PRC2 Complex Subunits Dpf2 and Eed Antagonistically Converge on Tbx3 to Control ESC Differentiation. Cell Stem Cell, 24(1), 138-+
Open this publication in new window or tab >>The BAF and PRC2 Complex Subunits Dpf2 and Eed Antagonistically Converge on Tbx3 to Control ESC Differentiation
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2019 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 24, no 1, p. 138-+Article in journal (Refereed) Published
Abstract [en]

BAF complexes are composed of different subunits with varying functional and developmental roles, although many subunits have not been examined in depth. Here we show that the Baf45 subunit Dpf2 maintains pluripotency and ESC differentiation potential. Dpf2 co-occupies enhancers with Oct4, Sox2, p300, and the BAF subunit Brg1, and deleting Dpf2 perturbs ESC self-renewal, induces repression of Tbx3, and impairs mesendodermal differentiation without dramatically altering Brg1 localization. Mesendodermal differentiation can be rescued by restoring Tbx3 expression, whose distal enhancer is positively regulated by Dpf2-dependent H3K27ac maintenance and recruitment of pluripotency TFs and Brg1. In contrast, the PRC2 subunit Eed binds an intragenic Tbx3 enhancer to oppose Dpf2-dependent Tbx3 expression and mesendodermal differentiation. The PRC2 subunit Ezh2 likewise opposes Dpf2-dependent differentiation through a distinct mechanism involving Nanog repression. Together, these findings delineate distinct mechanistic roles for specific BAF and PRC2 subunits during ESC differentiation.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Developmental Biology
Identifiers
urn:nbn:se:kth:diva-241316 (URN)10.1016/j.stem.2018.12.001 (DOI)000454836900015 ()30609396 (PubMedID)2-s2.0-85058662637 (Scopus ID)
Note

QC 20190125

Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved
Tapia-Paez, I., Asad, S., Taylan, F., Spalinskas, R., Anandashankar, A., Nordenskjold, M., . . . Bradley, M. (2018). Studies of keratinocyte-specific regulatory interactions by three-dimensional mapping with a focus on atopic dermatitis. Paper presented at 10th George Rajka International Symposium on Atopic Dermatitis, APR 11-13, 2018, Utrecht, NETHERLANDS. British Journal of Dermatology, 179(1), E33-E33
Open this publication in new window or tab >>Studies of keratinocyte-specific regulatory interactions by three-dimensional mapping with a focus on atopic dermatitis
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2018 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 179, no 1, p. E33-E33Article in journal (Refereed) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:kth:diva-232913 (URN)000439461600070 ()
Conference
10th George Rajka International Symposium on Atopic Dermatitis, APR 11-13, 2018, Utrecht, NETHERLANDS
Note

QC 20180808

Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
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