Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis

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Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis. / Kristensen, D. G.; Nielsen, J. E.; Jørgensen, A.; Skakkebæk, N. E.; Rajpert-De Meyts, E.; Almstrup, K.

In: British Journal of Cancer, Vol. 110, No. 3, 04.02.2014, p. 668-678.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Kristensen, DG, Nielsen, JE, Jørgensen, A, Skakkebæk, NE, Rajpert-De Meyts, E & Almstrup, K 2014, 'Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis', British Journal of Cancer, vol. 110, no. 3, pp. 668-678. https://doi.org/10.1038/bjc.2013.727

APA

Kristensen, D. G., Nielsen, J. E., Jørgensen, A., Skakkebæk, N. E., Rajpert-De Meyts, E., & Almstrup, K. (2014). Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis. British Journal of Cancer, 110(3), 668-678. https://doi.org/10.1038/bjc.2013.727

Vancouver

Kristensen DG, Nielsen JE, Jørgensen A, Skakkebæk NE, Rajpert-De Meyts E, Almstrup K. Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis. British Journal of Cancer. 2014 Feb 4;110(3):668-678. https://doi.org/10.1038/bjc.2013.727

Author

Kristensen, D. G. ; Nielsen, J. E. ; Jørgensen, A. ; Skakkebæk, N. E. ; Rajpert-De Meyts, E. ; Almstrup, K. / Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis. In: British Journal of Cancer. 2014 ; Vol. 110, No. 3. pp. 668-678.

Bibtex

@article{4803b374e4e84732957d170079e3189e,
title = "Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis",
abstract = "Background:Developmental arrest of fetal germ cells may lead to neoplastic transformation and formation of germ cell tumours via carcinoma in situ (CIS) cells. Normal fetal germ cell development requires complete erasure and re-establishment of DNA methylation. In contrast to normal spermatogonia, the genome of CIS cells remains unmethylated in the adult testis. We here investigated the possible active and passive pathways that can sustain the CIS genome hypomethylated in the adult testis.Methods:The levels of 5-methyl-cytosine (5mC) and 5-hydroxy-methyl-cytosine (5hmC) in DNA from micro-dissected CIS cells were assessed by quantitative measurements. The expression of TET1, TET2, APOBEC1, MBD4, APEX1, PARP1, DNMT1, DNMT3A, DNMT3B and DNMT3L in adult testis specimens with CIS and in human fetal testis was investigated by immunohistochemistry and immunofluorescence.Results:DNA from micro-dissected CIS cells contained very low levels of 5hmC produced by ten eleven translocation (TET) enzymes. CIS cells and fetal germ cells expressed the suggested initiator of active demethylation, APOBEC1, and the base excision repair proteins MBD4, APEX1 and PARP1, whereas TETs-the alternative initiators were absent. Both maintenance and de novo methyltransferases were detected in CIS cells.Conclusion:The data are consistent with the presence of an active DNA de-methylation pathway in CIS cells. The hypomethylated genome of CIS cells may contribute to phenotypic plasticity and invasive capabilities of this testicular cancer precursor.",
keywords = "5hmC, CIS, DNA demethylation, fetal germ cells",
author = "Kristensen, {D. G.} and Nielsen, {J. E.} and A. J{\o}rgensen and Skakkeb{\ae}k, {N. E.} and {Rajpert-De Meyts}, E. and K. Almstrup",
note = "Funding Information: The work herein was supported by the Research Fund of Rigshospitalet (to JEN, no. 9615.06.1.15), the Lundbeck Foundation (to ERM, no. R48-A4746) and The Danish Cancer Society (to ERM, no. R40-A2127-B1276). We are very grateful for the skilled technical work by Ana Ricci Nielsen, Brian Vendelbo Hansen and Betina F Nielsen. We thank Dr G Spagnoli for a generous gift of MAGE-A4 antibody, Dr K Okamoto for the generous gift of DNMT3L antibody, Dr PW Andrews for NTera2 cells, and Drs S Kitazawa and J Shipley for TCam-2 cells.",
year = "2014",
month = feb,
day = "4",
doi = "10.1038/bjc.2013.727",
language = "English",
volume = "110",
pages = "668--678",
journal = "The British journal of cancer. Supplement",
issn = "0007-0920",
publisher = "nature publishing group",
number = "3",

}

RIS

TY - JOUR

T1 - Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis

AU - Kristensen, D. G.

AU - Nielsen, J. E.

AU - Jørgensen, A.

AU - Skakkebæk, N. E.

AU - Rajpert-De Meyts, E.

AU - Almstrup, K.

N1 - Funding Information: The work herein was supported by the Research Fund of Rigshospitalet (to JEN, no. 9615.06.1.15), the Lundbeck Foundation (to ERM, no. R48-A4746) and The Danish Cancer Society (to ERM, no. R40-A2127-B1276). We are very grateful for the skilled technical work by Ana Ricci Nielsen, Brian Vendelbo Hansen and Betina F Nielsen. We thank Dr G Spagnoli for a generous gift of MAGE-A4 antibody, Dr K Okamoto for the generous gift of DNMT3L antibody, Dr PW Andrews for NTera2 cells, and Drs S Kitazawa and J Shipley for TCam-2 cells.

PY - 2014/2/4

Y1 - 2014/2/4

N2 - Background:Developmental arrest of fetal germ cells may lead to neoplastic transformation and formation of germ cell tumours via carcinoma in situ (CIS) cells. Normal fetal germ cell development requires complete erasure and re-establishment of DNA methylation. In contrast to normal spermatogonia, the genome of CIS cells remains unmethylated in the adult testis. We here investigated the possible active and passive pathways that can sustain the CIS genome hypomethylated in the adult testis.Methods:The levels of 5-methyl-cytosine (5mC) and 5-hydroxy-methyl-cytosine (5hmC) in DNA from micro-dissected CIS cells were assessed by quantitative measurements. The expression of TET1, TET2, APOBEC1, MBD4, APEX1, PARP1, DNMT1, DNMT3A, DNMT3B and DNMT3L in adult testis specimens with CIS and in human fetal testis was investigated by immunohistochemistry and immunofluorescence.Results:DNA from micro-dissected CIS cells contained very low levels of 5hmC produced by ten eleven translocation (TET) enzymes. CIS cells and fetal germ cells expressed the suggested initiator of active demethylation, APOBEC1, and the base excision repair proteins MBD4, APEX1 and PARP1, whereas TETs-the alternative initiators were absent. Both maintenance and de novo methyltransferases were detected in CIS cells.Conclusion:The data are consistent with the presence of an active DNA de-methylation pathway in CIS cells. The hypomethylated genome of CIS cells may contribute to phenotypic plasticity and invasive capabilities of this testicular cancer precursor.

AB - Background:Developmental arrest of fetal germ cells may lead to neoplastic transformation and formation of germ cell tumours via carcinoma in situ (CIS) cells. Normal fetal germ cell development requires complete erasure and re-establishment of DNA methylation. In contrast to normal spermatogonia, the genome of CIS cells remains unmethylated in the adult testis. We here investigated the possible active and passive pathways that can sustain the CIS genome hypomethylated in the adult testis.Methods:The levels of 5-methyl-cytosine (5mC) and 5-hydroxy-methyl-cytosine (5hmC) in DNA from micro-dissected CIS cells were assessed by quantitative measurements. The expression of TET1, TET2, APOBEC1, MBD4, APEX1, PARP1, DNMT1, DNMT3A, DNMT3B and DNMT3L in adult testis specimens with CIS and in human fetal testis was investigated by immunohistochemistry and immunofluorescence.Results:DNA from micro-dissected CIS cells contained very low levels of 5hmC produced by ten eleven translocation (TET) enzymes. CIS cells and fetal germ cells expressed the suggested initiator of active demethylation, APOBEC1, and the base excision repair proteins MBD4, APEX1 and PARP1, whereas TETs-the alternative initiators were absent. Both maintenance and de novo methyltransferases were detected in CIS cells.Conclusion:The data are consistent with the presence of an active DNA de-methylation pathway in CIS cells. The hypomethylated genome of CIS cells may contribute to phenotypic plasticity and invasive capabilities of this testicular cancer precursor.

KW - 5hmC

KW - CIS

KW - DNA demethylation

KW - fetal germ cells

U2 - 10.1038/bjc.2013.727

DO - 10.1038/bjc.2013.727

M3 - Journal article

C2 - 24292451

AN - SCOPUS:84893744140

VL - 110

SP - 668

EP - 678

JO - The British journal of cancer. Supplement

JF - The British journal of cancer. Supplement

SN - 0007-0920

IS - 3

ER -

ID: 284205217