title: Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling.
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.
authors.affiliation: Institute of Pathology, University of Wuerzburg, Josef-Schneider-Strasse 2, D-97080 Wuerzburg, Germany.
authors.forename: Askar
authors.initials: A
authors.lastname: Akimzhanov
authors.forename: Laszlo
authors.initials: L
authors.lastname: Krenacs
authors.forename: Timm
authors.initials: T
authors.lastname: Schlegel
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein-Hessling
authors.forename: Enikö
authors.initials: E
authors.lastname: Bagdi
authors.forename: Eva
authors.initials: E
authors.lastname: Stelkovics
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.forename: Sergei
authors.initials: S
authors.lastname: Chuvpilo
authors.forename: Philipp
authors.initials: P
authors.lastname: Wilke
authors.forename: Andris
authors.initials: A
authors.lastname: Avots
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: Hans-Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Alois
authors.initials: A
authors.lastname: Palmetshofer
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006689:Hodgkin Disease / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D016329:Sp1 Transcription Factor