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The work was supported by the following: Ministerio de Economia y Competitividad, SAF2012-38078 (OB); Ministerio de Economia y Competitividad, SAF2015-64344-R (OB); Fundacion La Caixa 2016-052.407 (RA); Institute de Salud Carlos III RD/120036/0054.AB is supported by grants from the Fondation ARC pour la Reserche sur le Cancer, Ligue National Contre le Cancer and Institut National du Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to thank to Dr. Pedro M. Fernandez for the kind gift of the anti-AHR antibody. This work was supported by grants from the Ministerio de Economia y competitividad (MINECO) SAF2012-38078, SAF2015-64244-R, La Caixa 2016-052.407 and from the Instituto de Salud Carlos III RD12/0036/0054. AB is supported by grants from the Fondation ARC pour la Reserche sur le Cancer, Ligue National Contre le Cancer and Institut National du Cancer. The data set has been deposited in ArrayExpress accession number E-MTAB-5105.

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ChIP-Seq analysis identifies p27(Kip1)-target genes involved in cell adhesion and cell signalling in mouse embryonic fibroblasts.

Publicado en:Plos One. 12 (11): e0187891- - 2017-11-20 12(11), DOI: 10.1371/journal.pone.0187891

Autores: Biçer A, Orlando S, Islam ABMMK, Gallastegui E, Besson A, Aligué R, Bachs O, Pujol MJ

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The protein p27Kip1 (p27), a member of the Cip-Kip family of cyclin-dependent kinase inhibitors, is involved in tumorigenesis and a correlation between reduced levels of this protein in human tumours and a worse prognosis has been established. Recent reports revealed that p27 also behaves as a transcriptional regulator. Thus, it has been postulated that the development of tumours with low amounts of p27 could be propitiated by deregulation of transcriptional programs under the control of p27. However, these programs still remain mostly unknown. The aim of this study has been to define the transcriptional programs regulated by p27 by first identifying the p27-binding sites (p27-BSs) on the whole chromatin of quiescent mouse embryonic fibroblasts. The chromatin regions associated to p27 have been annotated to the most proximal genes and it has been considered that the expression of these genes could by regulated by p27. The identification of the chromatin p27-BSs has been performed by Chromatin Immunoprecipitation Sequencing (ChIP-seq). Results revealed that p27 associated with 1839 sites that were annotated to 1417 different genes being 852 of them protein coding genes. Interestingly, most of the p27-BSs were in distal intergenic regions and introns whereas, in contrast, its association with promoter regions was very low. Gene ontology analysis of the protein coding genes revealed a number of relevant transcriptional programs regulated by p27 as cell adhesion, intracellular signalling and neuron differentiation among others. We validated the interaction of p27 with different chromatin regions by ChIP followed by qPCR and demonstrated that the expressions of several genes belonging to these programs are actually regulated by p27. Finally, cell adhesion assays revealed that the adhesion of p27-/- cells to the plates was much higher that controls, revealing a role of p27 in the regulation of a transcriptional program involved in cell adhesion.

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