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THE STEM CELL NICHE

Hypoxia Causes Downregulation of Mismatch Repair System and Genomic Instability in Stem Cells

Farmacología Molecular, Centro de Investigación Príncipe Felipe, Valencia, Spain

Key Words. Mismatch repair • Hypoxia-inducible factor • Microsatellite instability • Hypoxia • Cancer stem cells

Correspondence: Correspondence: José-María Sánchez-Puelles, Ph.D., Department Farmacología Molecular, Fundación Valenciana Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain. Telephone: 34963289680; Fax: 34963289701; e-mail: jmsp{at}cipf.es; or Francisco Javier Rodríguez-Jiménez, Farmacología Molecular, Centro de Investigación Príncipe Felipe, Valencia, Spain. Telephone: +34963289680; Fax: 34963289701; e-mail: frodriguez{at}cipf.es

Received on December 10, 2007; accepted for publication on May 18, 2008.

First published online in STEM CELLS EXPRESS  May 29, 2008.

The DNA mismatch repair (MMR) system maintains genomic integrity by correcting replication errors: its malfunction causes genomic instability in several tumor types. Hypoxia-inducible factor-1 (HIF1), the major regulator of the processes that occur in hypoxia and certain epigenetic events downregulate the expression of MMR genes in cancer cells. However, there is a lack of information regarding MMR regulation and the genetic stability of stem cells under hypoxic conditions. The expression of the MMR system is downregulated in murine and human stem cells cultured in hypoxia, which correlates with lower DNA repair activity in neural stem cells. We observed, through the use of short hairpin loop RNAi expression constructs, that HIF1 positively regulated MLH1 and MSH6 when the C17.2 neural stem cells were exposed to short-term hypoxia. However, in prolonged exposure to oxygen depletion, the reduced transcriptional activation of MMR genes was directed by specific epigenetic events. Chromatin immunoprecipitation experiments showed a hypoacetylated/hypermethylated histone H3 and lower SP1 binding within MLH1 and MSH6 adjacent promoter regions. Treatment with the histone deacetylase inhibitor trichostatin A increased histone H3 acetylation and SP1 occupancy and enhanced MMR expression. Sequencing of microsatellite markers revealed genomic instability in the murine and human stem cells grown under hypoxia. Thus, the present article reports, for the first time in the stem cell field, experimental data that indicate that hypoxic niches are an environment in which stem cells might undergo genomic instability, which could lie at the origin of subpopulations with cancer stem cell properties.

Disclosure of potential conflicts of interest is found at the end of this article.