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Dissecting epigenetic silencing complexity in the mouse lung cancer suppressor gene cadm1

 
: Reamon-Büttner, Stella Marie; Borlak, Jürgen

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Volltext urn:nbn:de:0011-n-2063622 (1.3 MByte PDF)
MD5 Fingerprint: 51f3fc7f929594fbdb4e4bd606d1deb9
Erstellt am: 21.8.2012


PLoS one. Online journal 7 (2012), Nr.6, Art. e38531
http://www.pubmedcentral.nih.gov/tocrender.fcgi?action=archive&journal=440
ISSN: 1932-6203
Englisch
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer ITEM ()
Cadm1; tumor suppressor gene; promoter hypermethylation; cancer cell lines; lungs; cancer; transgenic mice

Abstract
Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and a mong the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3), and opposing histone modification marks (H3K4me3 and H3K27me3) all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and 'bivalent' histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer.

: http://publica.fraunhofer.de/dokumente/N-206362.html