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Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway.

ABSTRACT: The urokinase receptor (u-PAR) which is largely regulated at the transcriptional level has been implicated in tumor progression. In this study, we explored the epigenetic regulation of u-PAR and showed that the histone variant H2A.Z negatively regulates its expression in multiple cell lines. Chromatin immunoprecipitation assays revealed that H2A.Z was enriched at previously characterized u-PAR-regulatory regions (promoter and a downstream enhancer) and dissociates upon activation of gene expression by phorbol ester (PMA). Using specific chemical and dominant negative expression constructs, we show that the MEK-ERK signaling pathway terminating at AP-1 transcription factors intersects with the epigenetic control of u-PAR expression by H2A.Z. Furthermore, we demonstrate that two other AP-1 targets (MMP9 gene and miR-21 microRNA) are also H2A.Z regulated. In conclusion, our work demonstrates that (i) the expression of two genes and a microRNA all implicated in tumor progression are directly regulated by H2A.Z and (ii) MEK-ERK signaling terminating at AP-1 intersects with the epigenetic control of target gene expression by H2A.Z.

SUBMITTER: Chauhan S

PROVIDER: S-EPMC3258129 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway.

Chauhan Santosh S Boyd Douglas D DD

Nucleic acids research 20110921 2

The urokinase receptor (u-PAR) which is largely regulated at the transcriptional level has been implicated in tumor progression. In this study, we explored the epigenetic regulation of u-PAR and showed that the histone variant H2A.Z negatively regulates its expression in multiple cell lines. Chromatin immunoprecipitation assays revealed that H2A.Z was enriched at previously characterized u-PAR-regulatory regions (promoter and a downstream enhancer) and dissociates upon activation of gene express ...[more]

PMID: 21937508

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Project description:Activation of Map kinase/Erk signalling downstream of fibroblast growth factor (Fgf) tyrosine kinase receptors regulates gene expression required for mesoderm induction and patterning of the anteroposterior axis during Xenopus development. We have proposed that a subset of Fgf target genes are activated in the embyo in response to inhibition of a transcriptional repressor. Here we investigate the hypothesis that Cic (Capicua), which was originally identified as a transcriptional repressor negatively regulated by receptor tyrosine kinase/Erk signalling in Drosophila, is involved in regulating Fgf target gene expression in Xenopus. We characterise Xenopus Cic and show that it is widely expressed in the embryo. Fgf overexpression or ectodermal wounding, both of which potently activate Erk, reduce Cic protein levels in embryonic cells. In keeping with our hypothesis, we show that Cic knockdown and Fgf overexpression have overlapping effects on embryo development and gene expression. Transcriptomic analysis identifies a cohort of genes that are up-regulated by Fgf overexpression and Cic knockdown. We investigate two of these genes as putative targets of the proposed Fgf/Erk/Cic axis: fos and rasl11b, which encode a leucine zipper transcription factor and a ras family GTPase, respectively. We identify Cic consensus binding sites in a highly conserved region of intron 1 in the fos gene and Cic sites in the upstream regions of several other Fgf/Cic co-regulated genes, including rasl11b. We show that expression of fos and rasl11b is blocked in the early mesoderm when Fgf and Erk signalling is inhibited. In addition, we show that fos and rasl11b expression is associated with the Fgf independent activation of Erk at the site of ectodermal wounding. Our data support a role for a Fgf/Erk/Cic axis in regulating a subset of Fgf target genes during gastrulation and is suggestive that Erk signalling is involved in regulating Cic target genes at the site of ectodermal wounding.

Dataset Information

Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway.

Publications

Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway.

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