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Biochim Biophys Acta. 2014 Nov;1839(11):1341-50. doi: 10.1016/j.bbagrm.2014.07.010. Epub 2014 Aug 8.

Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells.

Author information

1
Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland; Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden; Institute of Computer Science, Polish Academy of Sciences, Warszawa, Poland. Electronic address: kruczyk@gmail.com.
2
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Poland. Electronic address: p.przanowski@nencki.gov.pl.
3
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Poland. Electronic address: m.dabrowski@nencki.gov.pl.
4
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Poland. Electronic address: kswiatek@nencki.gov.pl.
5
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Poland. Electronic address: j.mieczkowski@nencki.gov.pl.
6
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: ola.wallerman@imbim.uu.se.
7
Faculty of Pharmacy, Medical University of Gdansk, Poland. Electronic address: 7743@gumed.edu.pl.
8
Faculty of Pharmacy, Medical University of Gdansk, Poland. Electronic address: arpiotr@gumed.edu.pl.
9
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: claes.wadelius@igp.uu.se.
10
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Poland. Electronic address: B.Kaminska@nencki.gov.pl.
11
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden; Institute of Computer Science, Polish Academy of Sciences, Warszawa, Poland. Electronic address: jan.komorowski@lcb.uu.se.

Abstract

BACKGROUND:

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown.

RESULTS:

We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells.

CONCLUSIONS:

Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.

KEYWORDS:

Epigenetic modification; Glioma; Stat3; Stat3 gene regulatory network; Transcriptome–epigenome interaction; Whole genome Stat3 occupancy

PMID:
25111868
DOI:
10.1016/j.bbagrm.2014.07.010
[Indexed for MEDLINE]
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