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Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia
Örebro University Hospital. Department of Laboratory Medicine.
Örebro University Hospital. Department of Laboratory Medicine.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine; Örebro University hospital.
Department of Nutritional sciences; Dell pediatric Research Institute; University of Texas; Austin, Usa.
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2013 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, no 3, 303-316 p.Article in journal (Refereed) Published
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 a (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.

Place, publisher, year, edition, pages
2013. Vol. 8, no 3, 303-316 p.
Keyword [en]
FOLR1, PCFT, RFC1 80G > A, homocysteine, tissue-specific DNA methylation, GpG island, NTD
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-35872DOI: 10.4161/epi.23988ISI: 000315923300008OAI: oai:DiVA.org:oru-35872DiVA: diva2:736583
Note

Funding agencies:

Lions cancerfond

Nyckelfonden

Orebro lans landsting

NIH Grant numbers: HD067244 ES021390

State Key Development Program for Basic Research, People's Republic of China Grant numbers: 2007CB5119001 

Available from: 2014-08-07 Created: 2014-08-07 Last updated: 2017-10-18Bibliographically approved
In thesis
1. DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
Open this publication in new window or tab >>DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DNA methylation is an epigenetic mechanism that regulates the gene transcription. Folate is used in cellular synthesis of methyl groups, nucleic acids and amino acids. In complex diseases like cancer and neural tube defects (NTD), various genetic and epigenetic alterations can be found that disrupt the normal cell function. The main goals of this thesis were to analyze whether the genes responsible for the folate transport (FOLR1, PCFT, and RFC1) could be regulated by DNA methylation in placenta, blood leukocytes and colorectal cancer. We also addressed the genome-wide DNA methylation changes in colorectal cancer andcervical cancer.We found that changes in the methylated fraction of the RFC1 gene were dependent on the RFC1 80G>A polymorphism in placental specimens with NTDs and blood leukocytes from subjects with high homocysteine (Paper I). In colorectal cancer, the greatest difference in DNA methylation was observed in the RFC1 gene and was related to a lower protein expression (Paper II).In Paper III and IV we studied the DNA methylated fraction using a high-density array. Paper III was focused on genes in the DNA repair pathway and frequently mutated in colorectal cancer. We found that aberrant methylation in the DNA mismatch repair genes was not a frequent event in colorectal cancer and we identified five candidate biomarker genes in colorectal cancer, among them the GPC6 and DCLRE1C genes. In Paper IV, we found hypomethylation of genes involved in the immune system in cervical cancer specimens compared to healthy cervical scrapes and we identified twenty four candidate genes for further evaluation ofclinical value.In conclusion, the work of this thesis filled a relevant knowledge gap regarding the role of differential methylation of the folate transport genes in NTD and colorectal cancer. This thesis work also provided insights into the functional role of DNA methylation in cancer specific pathways and identified potential novel biomarker genes.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2014. 67 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 100
Keyword
DNA methylation, CRC, placenta, cervix, leukocytes, T-DMRs, folate, array, expression
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32599 (URN)978-91-7668-986-8 (ISBN)
Public defence
2014-01-31, Wilandersalen, Universitetssjukhuset, S. Grev Rosengatan, 703 62 Örebro, 09:15 (English)
Opponent
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Available from: 2013-12-02 Created: 2013-12-02 Last updated: 2017-10-17Bibliographically approved

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Farkas, Sanja A.Böttiger, Anna K.Isaksson, Helena S.Ren, AiguoNilsson, Torbjorn K.
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Örebro University HospitalSchool of Health and Medical Sciences, Örebro University, Sweden
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Epigenetics
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