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  • 1. Bostrom, Adrian E.
    et al.
    Chatzittofis, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Ciuculete, Diana-Maria
    Flanagan, John N.
    Krattinger, Regina
    Bandstein, Marcus
    Mwinyi, Jessica
    Kullak-Ublick, Gerd A.
    Oberg, Katarina Gorts
    Arver, Stefan
    Schioth, Helgi B.
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes2019Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification ?Compulsive Sexual Behavior Disorder? is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD ? cg18222192 (MIR708)(p < 10E-05,p(FDR) = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, p(FDR) = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.

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  • 2. Carter, Jessica A.
    et al.
    Gorecki, Dariusz C.
    Mein, Charles A.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Hafizi, Sassan
    CpG dinucleotide-specific hypermethylation of the TNS3 gene promoter in human renal cell carcinoma2013Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, nr 7, s. 739-747Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tensin3 is a cytoskeletal regulatory protein that inhibits cell motility. Downregulation of the gene encoding Tensin3 (TNS3) in human renal cell carcinoma (RCC) may contribute to cancer cell metastatic behavior. We speculated that epigenetic mechanisms, e.g., gene promoter hypermethylation, might account for TNS3 downregulation. In this study, we identified and validated a TNS3 gene promoter containing a CpG island, and quantified the methylation level within this region in RCC. Using a luciferase reporter assay we demonstrated a functional minimal promoter activity for a 500-bp sequence within the TNS3 CpG island. Pyrosequencing enabled quantitative determination of DNA methylation of each CpG dinucleotide (a total of 43) in the TNS3 gene promoter. Across the entire analyzed CpG stretch, RCC DNA showed a higher methylation level than both non-tumor kidney DNA and normal control DNA. Out of all the CpGs analyzed, two CpG dinucleotides, specifically position 2 and 8, showed the most pronounced increases in methylation levels in tumor samples. Furthermore, CpG-specific higher methylation levels were correlated with lower TNS3 gene expression levels in RCC samples. In addition, pharmacological demethylation treatment of cultured kidney cells caused a 3-fold upregulation of Tensin3 expression. In conclusion, these results reveal a differential methylation pattern in the TNS3 promoter occurring in human RCC, suggesting an epigenetic mechanism for aberrant Tensin downregulation in human kidney cancer.

  • 3. Farkas, Sanja A
    et al.
    Böttiger, Anna K
    Isaksson, Helena S
    Finnell, Richard H
    Ren, Aiguo
    Nilsson, Torbjörn K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Örebro Univ Hosp, Dept Lab Med, Örebro, Sweden.
    Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia2013Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, nr 3, s. 303-316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR's) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.

  • 4.
    Farkas, Sanja A
    et al.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro.
    Milutin-Gašperov, Nina
    Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
    Grce, Magdalena
    Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
    Nilsson, Torbjörn K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer2013Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, nr 11, s. 1213-1225Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The oncogenic human papilloma viruses (HPVs) are associated with precancerous cervical lesions and development of cervical cancer. The DNA methylation signatures of the host genome in normal, precancerous and cervical cancer tissue may indicate tissue-specific perturbation in carcinogenesis. The aim of this study was to identify new candidate genes that are differentially methylated in squamous cell carcinoma compared with DNA samples from cervical intraepithelial neoplasia grade 3 (CIN3) and normal cervical scrapes. The Illumina Infinium HumanMethylation450 BeadChip method identifies genome-wide DNA methylation changes in CpG islands, CpG shores and shelves. Our findings showed an extensive differential methylation signature in cervical cancer compared with the CIN3 or normal cervical tissues. The identified candidate biomarker genes for cervical cancer represent several types of mechanisms in the cellular machinery that are epigenetically deregulated by hypermethylation, such as membrane receptors, intracellular signaling and gene transcription. The results also confirm extensive hypomethylation of genes in the immune system in cancer tissues. These insights into the functional role of DNA methylome alterations in cervical cancer could be clinically applicable in diagnostics and prognostics, and may guide the development of new epigenetic therapies.

  • 5. Farkas, Sanja A.
    et al.
    Sorbe, Bengt G.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Epigenetic changes as prognostic predictors in endometrial carcinomas2017Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 12, nr 1, s. 19-26Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.

  • 6.
    Harlid, Sophia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
    Xu, Zongli
    Kirk, Erin
    Wilson, Lauren E.
    Troester, Melissa A.
    Taylor, Jack A.
    Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study2019Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, nr 2, s. 146-157Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10-7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

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  • 7. Lindqvist, Breezy M.
    et al.
    Wingren, Sten
    Motlagh, Parviz Behnam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, Torbjörn K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Whole genome DNA methylation signature of HER2-positive breast cancer2014Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, nr 8, s. 1149-1162Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.

  • 8. Lindqvist, Breezy Malakkaran
    et al.
    Farkas, Sanja A
    Wingren, Sten
    Nilsson, Torbjörn K
    School of Health and Medical Sciences; Örebro University; Örebro, Sweden; Department of Laboratory Medicine; Örebro University Hospital; Örebro, Sweden.
    DNA methylation pattern of the SLC25A43 gene in breast cancer2012Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 7, nr 3, s. 300-306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Solute carrier family 25A member 43 (SLC25A43) gene is a putative tumor suppressor gene that undergoes loss of heterozygosity (LOH) in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Also, knockdown of SLC25A43 in cell lines influences cell turnover and metabolism. Absence of mutations in this gene in breast cancers prompted us to study methylation as an alternate mechanism for gene inactivation of this X encoded gene. Quantification of CpG site methylation using pyrosequencing was performed upstream of the SLC25A43 gene and at its 5' end in a cohort of breast tumor tissues (n = 80, HER2 positive or negative) with different SLC25A43 gene deletion status. Compared with control tissue, cancer tissues had lower levels of methylation at the 5' and 3' shores of the gene. Cancer tissues with no deletion in the SLC25A43 gene (Del (-)) had higher methylation in the CpG island (CGI) of the gene than cancers carrying the deletion (Del (+)). Methylation in the CGI of the SLC25A43 gene was negatively correlated with age at diagnosis. In HER2 positive breast cancer, ER negativity and lymph node positivity was associated with higher methylation in the CGI and in the adjacent shores of this gene. Our results suggest that methylation in the CGI of the SLC25A43 gene could be an alternate mechanism of gene silencing in the absence of LOH. Also, associations between site-specific methylation and clinicopathological parameters suggest that epigenetic changes in SLC25A43 gene could be of importance in breast carcinogenesis.

  • 9.
    Myte, Robin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sundkvist, Anneli
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Harlid, Sophia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort2019Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, nr 7, s. 649-659Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

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