Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling

Askar Akimzhanov, L. Krenács, Timm Schlegel, Stefan Klein-Hessling, E. Bagdi, Eva Stelkovics, Eisaku Kondo, Sergei Chuvpilo, Philipp Wilke, Andris Avots, Stefan Gattenlöhner, Hans Konrad Müller-Hermelink, Alois Palmetshofer, Edgar Serfling

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Abstract

The nuclear factor of activated T cell 1 (Nfatc1) locus is a common insertion site for murine tumorigenic retroviruses, suggesting a role of transcription factor NFATc1 in lymphomagenesis. Although NFATc1 is expressed in most human primary lymphocytes and mature human T- and B-cell neoplasms, we show by histochemical stainings that NFATc1 expression is suppressed in anaplastic large cell lymphomas and classical Hodgkin's lymphomas (HLs). In HL cell lines, NFATc1 silencing correlated with a decrease in histone H3 acetylation, H3-K4 trimethylation, and Sp1 factor binding but with an increase in HP1 binding to the NFATC1 P1 promoter. Together with DNA hypermethylation of the NFATC1 P1 promoter, which we detected in all anaplastic large cell lymphoma and many HL lines, these observations reflect typical signs of transcriptional silencing. In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites. Together with the under-representation of Sp1 at the NFATC1 P1 promoter in HL cells, this suggests that Sp1 factors can protect P1 DNA methylation in a directional manner. Blocking immunoreceptor signaling led to NFATC1 P1 promoter silencing and to a decrease in H3 acetylation and H3-K4 methylation but not DNA methylation. This shows that histone modifications precede the DNA methylation in NFATC1 promoter silencing.

Original languageEnglish
Pages (from-to)215-224
Number of pages10
JournalAmerican Journal of Pathology
Volume172
Issue number1
DOIs
Publication statusPublished - Jan 2008

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NFATC Transcription Factors
Epigenomics
Lymphoma
Hodgkin Disease
DNA Methylation
Anaplastic Large-Cell Lymphoma
Acetylation
Methylation
Histone Code
DNA
Retroviridae
Histones
B-Lymphocytes
Transcription Factors
Binding Sites
Lymphocytes
Staining and Labeling
Cell Line

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling. / Akimzhanov, Askar; Krenács, L.; Schlegel, Timm; Klein-Hessling, Stefan; Bagdi, E.; Stelkovics, Eva; Kondo, Eisaku; Chuvpilo, Sergei; Wilke, Philipp; Avots, Andris; Gattenlöhner, Stefan; Müller-Hermelink, Hans Konrad; Palmetshofer, Alois; Serfling, Edgar.

In: American Journal of Pathology, Vol. 172, No. 1, 01.2008, p. 215-224.

Research output: Contribution to journalArticle

Akimzhanov, A, Krenács, L, Schlegel, T, Klein-Hessling, S, Bagdi, E, Stelkovics, E, Kondo, E, Chuvpilo, S, Wilke, P, Avots, A, Gattenlöhner, S, Müller-Hermelink, HK, Palmetshofer, A & Serfling, E 2008, 'Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling', American Journal of Pathology, vol. 172, no. 1, pp. 215-224. https://doi.org/10.2353/ajpath.2008.070294
Akimzhanov, Askar ; Krenács, L. ; Schlegel, Timm ; Klein-Hessling, Stefan ; Bagdi, E. ; Stelkovics, Eva ; Kondo, Eisaku ; Chuvpilo, Sergei ; Wilke, Philipp ; Avots, Andris ; Gattenlöhner, Stefan ; Müller-Hermelink, Hans Konrad ; Palmetshofer, Alois ; Serfling, Edgar. / Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling. In: American Journal of Pathology. 2008 ; Vol. 172, No. 1. pp. 215-224.
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