DNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cells

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dc.contributor.authorBariševs, Mihails
dc.contributor.authorInashkina, Inna
dc.contributor.authorSalmina, Kristine
dc.contributor.authorHuna, Anda
dc.contributor.authorJackson, Thomas R.
dc.contributor.authorĒrenpreisa, Jekaterina
dc.contributor.institutionInstitute of Microbiology and Virology
dc.date.accessioned2021-04-20T08:40:01Z
dc.date.available2021-04-20T08:40:01Z
dc.date.issued2018-02-01
dc.descriptionFunding Information: Dr. Bogdanova-Jatniece is acknowledged for sharing the sequences for Sox2 RT-qPCR. The authors thank Prof. MS Cragg for reading the manuscript. The study was supported by the Europe Social Fund Project, project No. 2013/0023/1DP/1.1.1.2.0/13/APIA/VIAA/037. The publishing costs are covered by the Riga Stradins University. Funding Information: The study was supported by the Europe Social Fund Project, project No. 2013/0023/1DP/1.1.1.2.0/13/APIA/VIAA/037. The publishing costs are covered by the Riga Stradins University. Publisher Copyright: © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.
dc.description.abstractThe epigenetic mechanisms underlying chemoresistance in cancer cells resulting from drug-induced reversible senescence are poorly understood. Chemoresistant ESC-like embryonal carcinoma PA1 cells treated with etoposide (ETO) were previously found to undergo prolonged G2 arrest with transient p53-dependent upregulation of opposing fate regulators, p21CIP1 (senescence) and OCT4A (self-renewal). Here we report on the analysis of the DNA methylation state of the distal enhancer (DE) and proximal enhancer (PE) of the Oct4A gene during this dual response. When compared to non–treated controls the methylation level increased from 1.3% to 12.5% and from 3% to 19.4%, in the DE and PE respectively. It included CpG and non-CpG methylation, which was not chaotic but presented two patterns in each enhancer. Discorrelating with methylation of enhancers, the transcription of Oct4A increased, however, a strong expression of the splicing form Oct4B was also induced, along with down-regulation of the Oct4A partners of in the pluripotency/self-renewal network Sox2 and Lin28. WB demonstrated disjoining of the OCT4A protein from the chromatin-bound fraction. In survival clones, methylation of the DE was considerably erased, while some remnant of methylation of the PE was still observed. The alternative splicing for Oct4B was reduced, Oct4A level insignificantly decreased, while the expression of Sox2 and Lin28 recovered, all three became proportionally above the control. These findings indicate the involvement of the transient patterned methylation of the Oct4A enhancers and alternative splicing in the adaptive regulation of cell fate choice during the p53-dependant dual state of reversible senescence in ESC-like cancer stem cells.en
dc.description.statusPeer reviewed
dc.format.extent5
dc.format.extent1177780
dc.identifier.citationBariševs, M, Inashkina, I, Salmina, K, Huna, A, Jackson, T R & Ērenpreisa, J 2018, 'DNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cells', Cell Cycle, vol. 17, no. 3, pp. 362-366. https://doi.org/10.1080/15384101.2018.1426412
dc.identifier.doi10.1080/15384101.2018.1426412
dc.identifier.issn1538-4101
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/3857
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85044219641&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofCell Cycle
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectalternative splicing
dc.subjectcell senescence
dc.subjectDNA damage
dc.subjectembryonal carcinoma
dc.subjectenhancer methylation
dc.subjectOct4A
dc.subjecttransient pluripotency suppression
dc.subjectwt TP53
dc.subject3.2 Clinical medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectMolecular Biology
dc.subjectDevelopmental Biology
dc.subjectCell Biology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleDNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cellsen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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